Publications by authors named "Dong-Qing Wei"

280 Publications

Screening of immune epitope in the proteome of the Dabie bandavirus, SFTS, to design a protein-specific and proteome-wide vaccine for immune response instigation using an immunoinformatics approaches.

Comput Biol Med 2022 Aug 7;148:105893. Epub 2022 Aug 7.

Department of Bioinformatics and Biological Statistics, School of Life Sciences and Biotechnology, Shanghai Jiao Tong University, Shanghai, 200240, PR China; Zhongjing Research and Industrialization Institute of Chinese Medicine, Zhongguancun Scientific Park, Meixi, Nayang, Henan, 473006, PR China; Peng Cheng Laboratory, Vanke Cloud City Phase I Building 8, Xili Street, Nashan District, Shenzhen, Guangdong, 518055, PR China.

Tick-borne viruses are a major risk from tick bites, which could result in viral infectious diseases among animals and humans. Bunyavirus causes severe fever with thrombocytopenia syndrome (SFTS), with signs and symptoms including high fever, vomiting, diarrhea, thrombocytopenia (low platelet count), leukopenia (low white blood cell count), elevated liver enzyme levels, multiple organ failure, and has a 6%-30% case-fatality rate. To date no effective drug or vaccines are available thus need urgent research for therapeutics formulation. Hence, in this study, the computational meta-analysis approach was implemented that incorporates immunoinformatics to find potential B-cell, HTL (helper T lymphocytes) and T-cell epitopes derived from antigenic SFTS proteins to design multi-epitopes vaccines for the treatment of SFTS. The predicted T cell, B cell and HTL epitopes were shortlisted and checked for antigenic properties and allergenic features. The best epitopes were then joined together to model of multi-epitopes vaccines for specific proteins (replicase and glycoprotein) and proteome wide. The constructed models were validated using in silico molecular docking approach to evaluate binding potential of the designed best constructs with TLR3 (toll like receptor 3). Following the MEVC (multi-epitopes vaccine construct) injection, the response of the immune system was significantly stimulated, and anti-toxicity of induced antibodies was tremendously enhanced. Before being neutralized, the antigen titers remained high 5-10 days after injection of replicase, glycoprotein and proteome wide constructed vaccines. For each antigenic vaccine, a significant antibody response induction was observed. Further, in vivo trials are required to affirm the effectiveness of the constructed vaccine against SFTS.
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http://dx.doi.org/10.1016/j.compbiomed.2022.105893DOI Listing
August 2022

Virulence and Biofilm Inhibition of 3-Methoxycinnamic Acid against Agrobacterium tumefaciens.

J Appl Microbiol 2022 Aug 11. Epub 2022 Aug 11.

School of Pharmaceutical Sciences, Hainan University, 570228, Haikou, China.

Aims: In the current study the anti-virulence and anti-biofilm activities of the cinnamic acid derivative, 3-methoxycinnamic acid, was investigated against Agrobacterium tumefaciens.

Methods And Results: Based on the disc diffusion test and β-galactosidase activity assay, 3-methoxycinnamic acid was shown to interfere with the quorum sensing (QS) system of A. tumefaciens. Crystal violet staining assay, phenol-sulfuric acid method, Bradford protein assay and confocal laser scanning microscopy (CLSM) revealed that the biofilm formation of A. tumefaciens was inhibited after the treatment of 3-methoxycinnamic acid. Employing high performance liquid chromatography (HPLC) analysis of culture supernatant revealed that the production of 3-oxo-octanoylhomoserine lactone (3-oxo-C8-HSL) decreased concentration-dependently after treatment with 3-methoxycinnamic acid. Swimming and chemotaxis assays also indicated that 3-methoxycinnamic acid had a good effect on reducing the motility and chemotaxis of A. tumefaciens. In addition, the RT-qPCR, molecular docking and simulations further demonstrated that 3-methoxycinnamic acid could competitively inhibit the binding of 3-oxo-C8-HSL to TraR and down-regulate virulence-related genes.

Conclusions: 3-Methoxycinnamic acid is proved to have good anti-virulence and anti-biofilm activities against A. tumefaciens.

Significance And Impact Of The Study: This is the first study that investigates the anti-virulence and anti-biofilm activities of 3-methoxycinnamic acid against A. tumefaciens. With its potential QS-related virulence and biofilm inhibitory activities, 3-methoxycinnamic acid is expected to be developed as a potent pesticide or adjuvant for the prevention and treatment of crown gall caused by A. tumefaciens.
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http://dx.doi.org/10.1111/jam.15774DOI Listing
August 2022

Effect of Cholesterol on C99 Dimerization: Revealed by Molecular Dynamics Simulations.

Front Mol Biosci 2022 19;9:872385. Epub 2022 Jul 19.

State Key Laboratory of Microbial Metabolism, Joint Laboratory of International Cooperation in Metabolic and Developmental Sciences, Ministry of Education, Department of Bioinformatics and Biological Statistics, School of Life Sciences and Biotechnology, Shanghai Jiao Tong University, Shanghai, China.

C99 is the immediate precursor for amyloid beta (Aβ) and therefore is a central intermediate in the pathway that is believed to result in Alzheimer's disease (AD). It has been suggested that cholesterol is associated with C99, but the dynamic details of how cholesterol affects C99 assembly and the Aβ formation remain unclear. To investigate this question, we employed coarse-grained and all-atom molecular dynamics simulations to study the effect of cholesterol and membrane composition on C99 dimerization. We found that although the existence of cholesterol delays C99 dimerization, there is no direct competition between C99 dimerization and cholesterol association. In contrast, the existence of cholesterol makes the C99 dimer more stable, which presents a cholesterol binding C99 dimer model. Cholesterol and membrane composition change the dimerization rate and conformation distribution of C99, which will subsequently influence the production of Aβ. Our results provide insights into the potential influence of the physiological environment on the C99 dimerization, which will help us understand Aβ formation and AD's etiology.
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http://dx.doi.org/10.3389/fmolb.2022.872385DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9343951PMC
July 2022

Structural and molecular insights into the mechanism of resistance to enzalutamide by the clinical mutants in androgen receptor (AR) in castration-resistant prostate cancer (CRPC) patients.

Int J Biol Macromol 2022 Jul 26;218:856-865. Epub 2022 Jul 26.

Engineering Research Center of Cell & Therapeutic Antibody, School of Pharmacy, Shanghai Jiao Tong University, Shanghai 200240, China. Electronic address:

Androgen receptor (AR) is a key contributing element in the prostate cancer (PCa) instigation, progression and it is among the vastly discovered target for prostate cancer. Numerous mechanisms trigger the expansion of CRPC among which the aberrant AR gene is considered as the prime factor. Recently three essential substitutions H875Y, F877L, and T878A are reported to cause resistance to Enzalutamide. However, no detailed study is available to explore the key events that contribute to the resistance. Hence, considering the applicability of structural bioinformatics and molecular simulation-based methods in the current study, we assessed the impact of these mutations on the binding of Enzalutamide. Using a long-run simulation approach the binding stability, residues flexibility, hydrogen bonding, and protein compactness for each complex were determined to reveal the dynamic variations induced by these mutations. We discovered that the binding mode of Enzalutamide is altered by these mutations which misstarget the key residues required for the antagonistic activity. Molecular simulation of each complex revealed that the wild type H11 and H12 are more flexible moving outside and provides more volume for the ligand optimization. In the mutant complexes, the H12 remained tighter pushing out enzalutamide from the key residues which then essentially misstarget the correct orientation for the antagonist activity. The binding free energy (BFE) for the wild type was computed to be -59.92 ± 0.18 kcal/mol, for H875Y the BFE was -55.92 ± 0.18 kcal/mol, -54.82 ± 0.15 kcal/mol for F877L and -53.87 ± 0.18 kcal/mol for T878A, which further demonstrate that these mutations have destabilized the binding of enzalutamide. The proteins' motion and FEL further validated the aforementioned findings where the wild type reported different dynamic features than the mutant complexes. In conclusion, this study provides a structural basis for the resistance to Enzalutamide, which can be used to design novel effective drugs using structure-based and rationale approaches.
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http://dx.doi.org/10.1016/j.ijbiomac.2022.07.058DOI Listing
July 2022

Enhancer-LSTMAtt: A Bi-LSTM and Attention-Based Deep Learning Method for Enhancer Recognition.

Biomolecules 2022 07 17;12(7). Epub 2022 Jul 17.

State Key Laboratory of Microbial Metabolism, and School of Life Sciences and Biotechnology, Shanghai Jiao Tong University, Shanghai 200240, China.

Enhancers are short DNA segments that play a key role in biological processes, such as accelerating transcription of target genes. Since the enhancer resides anywhere in a genome sequence, it is difficult to precisely identify enhancers. We presented a bi-directional long-short term memory (Bi-LSTM) and attention-based deep learning method (Enhancer-LSTMAtt) for enhancer recognition. Enhancer-LSTMAtt is an end-to-end deep learning model that consists mainly of deep residual neural network, Bi-LSTM, and feed-forward attention. We extensively compared the Enhancer-LSTMAtt with 19 state-of-the-art methods by 5-fold cross validation, 10-fold cross validation and independent test. Enhancer-LSTMAtt achieved competitive performances, especially in the independent test. We realized Enhancer-LSTMAtt into a user-friendly web application. Enhancer-LSTMAtt is applicable not only to recognizing enhancers, but also to distinguishing strong enhancer from weak enhancers. Enhancer-LSTMAtt is believed to become a promising tool for identifying enhancers.
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http://dx.doi.org/10.3390/biom12070995DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9313278PMC
July 2022

Investigating the stabilisation of IFN-α2a by replica exchange molecular dynamics simulation.

J Mol Model 2022 Jul 26;28(8):232. Epub 2022 Jul 26.

Injection Laboratory, Shanghai Tofflon Science and Technology Co, Ltd, Shanghai, 201108, China.

Current biopharmaceutical drugs are mainly a class of peptides or proteins that play an essential role in the treatment of many diseases. Such peptides/proteins are usually thermally unstable and may lose their bioactivity when exposed to ambient conditions. Therefore, they are not suitable for long-term storage. Lyophilisation is the most common method to prolong shelf life of solid peptide/protein drugs; however, the freeze-drying process can lead to irreversible damage. In the present study, human interferon-alpha 2a (IFN-α2a) was selected as a model protein drug; four disaccharides (β-lactose, β-maltose, sucrose, and trehalose) were selected as bioactive protectants. We investigated the effects of different protectants on IFN-α2a under various ambient conditions (vacuum, dry state, and aqueous solution) using replica exchange molecular dynamics simulation. The protective effect of β-maltose on IFN-α2a was the highest in aqueous solution and dry state, β-lactose showed a poor protective effect in all three conditions, the performance of sucrose was good in all conditions, and trehalose showed a better protective effect under vacuum conditions and in aqueous solution. Disaccharides form H-bonds with water, thereby preventing water from the tertiary structure of proteins. Trehalose forms strong H-bonds with water which explains its extraordinary stability.
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http://dx.doi.org/10.1007/s00894-022-05212-wDOI Listing
July 2022

Diversity and novel mutations in membrane transporters of Mycobacterium tuberculosis.

Brief Funct Genomics 2022 Jul 23. Epub 2022 Jul 23.

State Key Laboratory of Microbial Metabolism, Shanghai-Islamabad-Belgrade Joint Innovation Center on Antibacterial Resistances, Joint Laboratory of International Cooperation in Metabolic and Developmental Sciences, Ministry of Education and School of Life Sciences and Biotechnology, Shanghai Jiao Tong University, Shanghai 200030, P.R. China.

Mycobacterium tuberculosis (MTB), the causative agent of tuberculosis (TB), encodes a family of membrane proteins belonging to Resistance-Nodulation-Cell Division (RND) permeases also called multidrug resistance pumps. Mycobacterial membrane protein Large (MmpL) transporters represent a subclass of RND transporters known to participate in exporting of lipid components across the cell envelope. These proteins perform an essential role in MTB survival; however, there are no data regarding mutations in MmpL, polyketide synthase (PKS) and acyl-CoA dehydrogenase FadE proteins from Khyber Pakhtunkhwa, Pakistan. This study aimed to screen mutations in transmembrane transporter proteins including MmpL, PKS and Fad through whole-genome sequencing (WGS) in local isolates of Khyber Pakhtunkhwa province, Pakistan. Fourteen samples were collected from TB patients and drug susceptibility testing was performed. However, only three samples were completely sequenced. Moreover, 209 whole-genome sequences of the same geography were also retrieved from NCBI GenBank to analyze the diversity of mutations in MmpL, PKS and Fad proteins. Among the 212 WGS (Accession ID: PRJNA629298, PRJNA629388, and ERR2510337-ERR2510345, ERR2510546-ERR2510645), numerous mutations in Fad (n = 756), PKS (n = 479), and MmpL (n = 306) have been detected. Some novel mutations were also detected in MmpL, PKS and acyl-CoA dehydrogenase Fad. Novel mutations including Asn576Ser in MmpL8, Val943Gly in MmpL9 and Asn145Asp have been detected in MmpL3. The presence of a large number of mutations in the MTB membrane may have functional consequences on proteins. However, further experimental studies are needed to elucidate the variants' effect on MmpL, PKS and FadE functions.
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http://dx.doi.org/10.1093/bfgp/elac018DOI Listing
July 2022

Structural and dynamic investigation of non-synonymous variations in Renin-AGT complex revealed altered binding via hydrogen-bonding network reprogramming to accelerate the hypertension pathway.

Chem Biol Drug Des 2022 Jun 22. Epub 2022 Jun 22.

The Key Laboratory of Biomedical Information Engineering of Ministry of Education, School of Life Sciences and Technology, Xi'an Jiaotong University, Xi'an, China.

Hypertension is one of the major issues worldwide and one of the main factors involved in heart and kidney failure. Angiotensinogen and renin are key components of the renin-angiotensin-aldosterone system, which plays an indispensable role in hypertension. The aim of this study was to find out the non-synonymous mutations and structure-based mutation-function correlation in the renin-AGT complex and reveal the most deleterious mutations to accelerated hypertension. In the current study, we employed computational modeling and molecular simulation approaches to demonstrate the impact of specific mutations in the REN-AGT interface in hypertension. Computational algorithms, that is, PhD-SNP, PolyPhen-1, MAPP, Sorting Intolerant from Tolerant, Screening of non-acceptable polymorphism, PredictSNP, PolyPhen-2, and Protein Analysis Through Evolutionary Relationships predicted 20 mutations as deleterious in AGT while only five mutations were confirmed as deleterious in the renin protein. Investigation of the bonding analysis revealed that two mutations S107L and V193F in renin altered the hydrogen-bonding paradigm at the interface site. Furthermore, exploration of structural-dynamic behaviors demonstrated by that these mutations also increases the structural stability to regulate the expression of disease pathway. The flexibility index of each residues and structural compactness analysis further validated the findings by portraying the difference in the dynamic behavior in contrast to the wild type. Binding energy calculations based on molecular mechanics/generalized Born surface area methods were used which further established the binding differences between the wild type, S107L, and V193F mutant variants. The total binding energy for wild type, S107L, and V193F was reported to be -27.79, -47.72, and -38.25, respectively. In conclusion, these two mutations increase the binding free energy alongside the docking score to enhance the binding between renin and AGT to overexpress this pathway in a hypertension disease condition. Patients with these mutations may be screened for potential therapeutic intervention.
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http://dx.doi.org/10.1111/cbdd.14107DOI Listing
June 2022

Repositioning of experimentally validated anti-breast cancer peptides to target FAK-PAX complex to halt the breast cancer progression: a biomolecular simulation approach.

Mol Divers 2022 May 30. Epub 2022 May 30.

Department of Bioinformatics and Biological Statistics, School of Life Sciences and Biotechnology, Shanghai Jiao Tong University, Shanghai, 200240, People's Republic of China.

FAK (focal adhesin kinase), a tyrosine kinase, plays an imperative role in cell-cell communication, particularly in cell signaling systems. It is a multi-functional signaling protein, which integrates and transduces signals into cancer cells through growth factor receptors or integrin and its interaction with Paxillin (PAX). The molecular processes by which FAK promotes the development and progression of cancer have progressively established the possible relationship between FAK-PAX complex in many types of cancer. The interaction of FAX and PAX is very important in breast cancer and thus acts as an essential biomarker for drugs, vaccines or peptide inhibitor designing. In this regard, computational approaches, particularly peptide designing to target the binding interface of the interacting partners, would greatly assist the design of peptide inhibitors against various cancer. Accordingly, in this present study, we screened 236 experimentally validated anti-breast cancer peptides using computational drugs repositioning approach to design peptides targeting the FAK-PAX complex. Using protein-peptide docking the binding site for the HP1 was confirmed and a total of 236 anti-breast cancer peptides were screened. Among the 236, only 12 peptides reported a docking score better than the control. From these 12, Magainin with the docking score - 103.8 ± 10.3 kcal/mol, NRC-07 with the docking score - 100.8 ± 16.5 kcal/mol, and Indolicidin with the docking score - 101.7 ± 3.9 kcal/mol, peptides potentially inhibit the FAX-PAX binding. Calculation of protein's motion and FEL revealed the binding and inhibitory behavior. Moreover, binding free energy (MM/GBSA) confirmed that Magainin exhibited the total binding energy - 53.28 kcal/mol, NRC-07 possessed the TBE - 44.16 kcal/mol, and Indolicidin reported the TBE of - 40.48 kcal/mol, thus explaining the inhibitory potential of these peptides. In conclusion, these peptides exhibit strong inhibitory potential and could abrogate the FAK-PAX complex in in vitro models and thus may relieve the burden of breast cancer.
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http://dx.doi.org/10.1007/s11030-022-10438-0DOI Listing
May 2022

Investigation of the binding and dynamic features of A.30 variant revealed higher binding of RBD for hACE2 and escapes the neutralizing antibody: A molecular simulation approach.

Comput Biol Med 2022 07 30;146:105574. Epub 2022 Apr 30.

Department of Bioinformatics and Biological Statistics, School of Life Sciences and Biotechnology, Shanghai Jiao Tong University, Shanghai, 200240, PR China; State Key Laboratory of Microbial Metabolism, Shanghai-Islamabad-Belgrade Joint Innovation Center on Antibacterial Resistances, Joint Laboratory of International Laboratory of Metabolic and Developmental Sciences, Ministry of Education and School of Life Sciences and Biotechnology, Shanghai Jiao Tong University, Shanghai, 200030, PR China; Peng Cheng Laboratory, Vanke Cloud City Phase I Building 8, Xili Street, Nashan District, Shenzhen, Guangdong, 518055, PR China; Zhongjing Research and Industrialization Institute of Chinese Medicine, Zhongguancun Scientific Park, Meixi, Nayang, Henan, 473006, PR China. Electronic address:

With the emergence of Delta and Omicron variants, many other important variants of SARS-CoV-2, which cause Coronavirus disease-2019, including A.30, are reported to increase the concern created by the global pandemic. The A.30 variant, reported in Tanzania and other countries, harbors spike gene mutations that help this strain to bind more robustly and to escape neutralizing antibodies. The present study uses molecular modelling and simulation-based approaches to investigate the key features of this strain that result in greater infectivity. The protein-protein docking results for the spike protein demonstrated that additional interactions, particularly two salt-bridges formed by the mutated residue Lys484, increase binding affinity, while the loss of key residues at the N terminal domain (NTD) result in a change to binding conformation with monoclonal antibodies, thus escaping their neutralizing effects. Moreover, we deeply studied the atomic features of these binding complexes through molecular simulation, which revealed differential dynamics when compared to wild type. Analysis of the binding free energy using MM/GBSA revealed that the total binding free energy (TBE) for the wild type receptor-binding domain (RBD) complex was -58.25 kcal/mol in contrast to the A.30 RBD complex, which reported -65.59 kcal/mol. The higher TBE for the A.30 RBD complex signifies a more robust interaction between A.30 variant RBD with ACE2 than the wild type, allowing the variant to bind and spread more promptly. The BFE for the wild type NTD complex was calculated to be -65.76 kcal/mol, while the A.30 NTD complex was estimated to be -49.35 kcal/mol. This shows the impact of the reported substitutions and deletions in the NTD of A.30 variant, which consequently reduce the binding of mAb, allowing it to evade the immune response of the host. The reported results will aid the development of cross-protective drugs against SARS-CoV-2 and its variants.
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http://dx.doi.org/10.1016/j.compbiomed.2022.105574DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9055381PMC
July 2022

A protein coupling and molecular simulation analysis of the clinical mutants of androgen receptor revealed a higher binding for Leupaxin, to increase the prostate cancer invasion and motility.

Comput Biol Med 2022 07 25;146:105537. Epub 2022 Apr 25.

Department of Urology, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China. Electronic address:

Recently a novel coactivator, Leupaxin (LPXN), has been reported to interact with Androgen receptor (AR) and play a significant role in the invasion and progression of prostate cancer. The interaction between AR and LPXN occurs in a ligand-dependent manner and has been reported that the LIM domain in the Leupaxin interacts with the LDB (ligand-binding domain) domain AR. However, no detailed study is available on how the LPXN interacts with AR and increases the (prostate cancer) PCa progression. Considering the importance of the novel co-activator, LPXN, the current study also uses state-of-the-art methods to provide atomic-level insights into the binding of AR and LPXN and the impact of the most frequent clinical mutations H874Y, T877A, and T877S on the binding and function of LPXN. Protein coupling analysis revealed that the three mutants favour the robust binding of LPXN than the wild type by altering the hydrogen bonding network. Further understanding of the binding variations was explored through dissociation constant prediction which demonstrated similar reports as the docking results. A molecular simulation approaches further revealed the dynamic features which reported variations in the dynamics stability, protein packing, hydrogen bonding network, and residues flexibility index. Furthermore, we also assessed the protein motion and free energy landscape which also demonstrated variations in the internal dynamics. The binding free energy calculation revealed -32.95 ± 0.17 kcal/mol for the wild type, for H874Y the total binding energy (BFE) was -36.69 ± 0.11 kcal/mol, for T877A the BFE was calculated to be -38.78 ± 0.17 kcal/mol while for T877S the BFE -41.16 ± 0.12 kcal/mol. This shows that the binding of LPXN is increased by these mutations which consequently increase the PCa invasion and motility. In conclusion, the current study helps in understanding the protein networks and particular the coupling of AR-LPXN in prostate cancer and is of great interest in deciphering the molecular mechanism of disease and therapeutics developments.
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http://dx.doi.org/10.1016/j.compbiomed.2022.105537DOI Listing
July 2022

The SARS-CoV-2 B.1.618 variant slightly alters the spike RBD-ACE2 binding affinity and is an antibody escaping variant: a computational structural perspective.

RSC Adv 2021 Sep 9;11(48):30132-30147. Epub 2021 Sep 9.

Department of Biochemistry and Molecular Biology, Dasman Diabetes Institute Kuwait.

Continuing reports of new SARS-CoV-2 variants have caused worldwide concern and created a challenging situation for clinicians. The recently reported variant B.1.618, which possesses the E484K mutation specific to the receptor-binding domain (RBD), as well as two deletions of Tyr145 and His146 at the N-terminal binding domain (NTD) of the spike protein, must be studied in depth to devise new therapeutic options. Structural variants reported in the RBD and NTD may play essential roles in the increased pathogenicity of this SARS-CoV-2 new variant. We explored the binding differences and structural-dynamic features of the B.1.618 variant using structural and biomolecular simulation approaches. Our results revealed that the E484K mutation in the RBD slightly altered the binding affinity through affecting the hydrogen bonding network. We also observed that the flexibility of three important loops in the RBD required for binding was increased, which may improve the conformational optimization and consequently binding of the new variant. Furthermore, we found that deletions of Tyr145 and His146 at the NTD reduced the binding affinity of the monoclonal antibody (mAb) 4A8, and that the hydrogen bonding network was significantly affected consequently. This data show that the new B.1.618 variant is an antibody-escaping variant with slightly altered ACE2-RBD affinity. Moreover, we provide insights into the binding and structural-dynamics changes resulting from novel mutations in the RBD and NTD. Our results suggest the need for further and studies that will facilitate the development of possible therapies for new variants such as B.1.618.
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http://dx.doi.org/10.1039/d1ra04694bDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9040812PMC
September 2021

Deep6mAPred: A CNN and Bi-LSTM-based deep learning method for predicting DNA N6-methyladenosine sites across plant species.

Methods 2022 08 25;204:142-150. Epub 2022 Apr 25.

School of Electrical Engineering, Shaoyang University, Shaoyang, Hunan 422000, China. Electronic address:

DNA N6-methyladenine (6mA) is a key DNA modification, which plays versatile roles in the cellular processes, including regulation of gene expression, DNA repair, and DNA replication. DNA 6mA is closely associated with many diseases in the mammals and with growth as well as development of plants. Precisely detecting DNA 6mA sites is of great importance to exploration of 6mA functions. Although many computational methods have been presented for DNA 6mA prediction, there is still a wide gap in the practical application. We presented a convolution neural network (CNN) and bi-directional long-short term memory (Bi-LSTM)-based deep learning method (Deep6mAPred) for predicting DNA 6mA sites across plant species. The Deep6mAPred stacked the CNNs and the Bi-LSTMs in a paralleling manner instead of a series-connection manner. The Deep6mAPred also employed the attention mechanism for improving the representations of sequences. The Deep6mAPred reached an accuracy of 0.9556 over the independent rice dataset, far outperforming the state-of-the-art methods. The tests across plant species showed that the Deep6mAPred is of a remarkable advantage over the state of the art methods. We developed a user-friendly web application for DNA 6mA prediction, which is freely available at http://106.13.196.152:7001/ for all the scientific researchers. The Deep6mAPred would enrich tools to predict DNA 6mA sites and speed up the exploration of DNA modification.
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http://dx.doi.org/10.1016/j.ymeth.2022.04.011DOI Listing
August 2022

Subtractive proteomics assisted therapeutic targets mining and designing ensemble vaccine against Candida auris for immune response induction.

Comput Biol Med 2022 06 1;145:105462. Epub 2022 Apr 1.

Department of Bioinformatics and Biological Statistics School of Life Sciences and Biotechnology, Shanghai Jiao Tong University, Shanghai, China; Peng Cheng Laboratory, Vanke Cloud City Phase I Building 8, Xili Street, Nashan District, Shenzhen, Guangdong, 518055, China; State Key Laboratory of Microbial Metabolism, Shanghai-Islamabad-Belgrade Joint Innovation Center on Antibacterial Resistances, Joint Laboratory of International Cooperation in Metabolic and Developmental Sciences, Ministry of Education and School of Life Sciences and Biotechnology, Shanghai Jiao Tong University, Shanghai, 200030, China. Electronic address:

The emergence of variants and the reports of co-infection caused by Candida auris in COVID-19 patients adds a further complication to the global pandemic situation. To date, no effective therapy is available for C. auris infections. Thus, characterization of therapeutic targets and designing effective vaccine candidates using subtractive proteomics and immune-informatics approaches is useful tool in controlling the emerging infections associated with SARS-CoV-2. In the current study, subtractive proteomics-assisted annotation of the vaccine targets was performed, which revealed seven vaccine targets. An immunoinformatic-driven approach was then employed to map protein-specific and proteome-wide immunogenic peptides (CTL, B cell, and HTL) for the design of multi-epitope vaccine candidates (MEVCs). The results demonstrated that the vaccine candidates possess strong antigenic features (>0.4 threshold score) and are classified as non-allergenic. Validation of the designed MEVCs through molecular docking, in-silico cloning, and immune simulation further demonstrated the efficacy of the vaccines by producing immune factor titers (ranging from 2500 to 16000 au/mL) i.e., IgM, IgG, IL-6, and Interferon-α. In conclusion, the current study provides a strong impetus in designing anti-fungal strategies against Candida auris.
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http://dx.doi.org/10.1016/j.compbiomed.2022.105462DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8971067PMC
June 2022

Blocking key mutated hotspot residues in the RBD of the omicron variant (B.1.1.529) with medicinal compounds to disrupt the RBD-hACE2 complex using molecular screening and simulation approaches.

RSC Adv 2022 Mar 4;12(12):7318-7327. Epub 2022 Mar 4.

Department of Bioinformatics and Biological Statistics, School of Life Sciences and Biotechnology, Shanghai Jiao Tong University Shanghai 200240 P.R. China

A new variant of SARS-CoV-2 known as the omicron variant (B.1.1.529) reported in South Africa with 30 mutations in the whole spike protein, among which 15 mutations are in the receptor-binding domain, is continuously spreading exponentially around the world. The omicron variant is reported to be highly contagious with antibody-escaping activity. The emergence of antibody-escaping variants is alarming, and thus the quick discovery of small molecule inhibitors is needed. Hence, the current study uses computational drug screening and molecular dynamics simulation approaches (replicated) to identify novel drugs that can inhibit the binding of the receptor-binding domain (RBD) with hACE2. Screening of the North African, East African and North-East African medicinal compound databases by employing a multi-step screening approach revealed four compounds, namely (-)-pipoxide (C1), 2-(-hydroxybenzyl) benzofuran-6-ol (C2), 1-(4-hydroxy-3-methoxyphenyl)-2-{4-[()-3-hydroxy-1-propenyl]-2-methoxyphenoxy}-1,3-propanediol (C3), and Rhein (C4), with excellent anti-viral properties against the RBD of the omicron variant. Investigation of the dynamics demonstrates stable behavior, good residue flexibility profiles, and structural compactness. Validation of the top hits using computational bioactivity analysis, binding free energy calculations and dissociation constant ( ) analysis also indicated the anti-viral properties of these compounds. In conclusion, this study will help in the design and discovery of novel drug therapeutics, which may be used against the emerging omicron variant of SARS-CoV-2.
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http://dx.doi.org/10.1039/d2ra00277aDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8982251PMC
March 2022

Potential Immunogenic Activity of Computationally Designed mRNA- and Peptide-Based Prophylactic Vaccines against MERS, SARS-CoV, and SARS-CoV-2: A Reverse Vaccinology Approach.

Molecules 2022 Apr 6;27(7). Epub 2022 Apr 6.

Foundation University Medical College, Foundation University Islamabad, Islamabad 46000, Pakistan.

The continued emergence of human coronaviruses (hCoVs) in the last few decades has posed an alarming situation and requires advanced cross-protective strategies against these pandemic viruses. Among these, Middle East Respiratory Syndrome coronavirus (MERS-CoV), Severe Acute Respiratory Syndrome coronavirus (SARS-CoV), and Severe Acute Respiratory Syndrome coronavirus-2 (SARS-CoV-2) have been highly associated with lethality in humans. Despite the challenges posed by these viruses, it is imperative to develop effective antiviral therapeutics and vaccines for these human-infecting viruses. The proteomic similarity between the receptor-binding domains (RBDs) among the three viral species offers a potential target for advanced cross-protective vaccine designs. In this study, putative immunogenic epitopes including Cytotoxic T Lymphocytes (CTLs), Helper T Lymphocytes (HTLs), and Beta-cells (B-cells) were predicted for each RBD-containing region of the three highly pathogenic hCoVs. This was followed by the structural organization of peptide- and mRNA-based prophylactic vaccine designs. The validated 3D structures of these epitope-based vaccine designs were subjected to molecular docking with human TLR4. Furthermore, the CTL and HTL epitopes were processed for binding with respective human Lymphocytes Antigens (HLAs). In silico cloning designs were obtained for the prophylactic vaccine designs and may be useful in further experimental designs. Additionally, the epitope-based vaccine designs were evaluated for immunogenic activity through immune simulation. Further studies may clarify the safety and efficacy of these prophylactic vaccine designs through experimental testing against these human-pathogenic coronaviruses.
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http://dx.doi.org/10.3390/molecules27072375DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9000378PMC
April 2022

Intermolecular Vibration Energy Transfer Process in Two CL-20-Based Cocrystals Theoretically Revealed by Two-Dimensional Infrared Spectra.

Molecules 2022 Mar 26;27(7). Epub 2022 Mar 26.

National Key Laboratory for Shock Wave and Detonation Physics Research, Institute of Fluid Physics, Chinese Academy of Engineering Physics, Mianyang 621999, China.

Inspired by the recent cocrystallization and theory of energetic materials, we theoretically investigated the intermolecular vibrational energy transfer process and the non-covalent intermolecular interactions between explosive compounds. The intermolecular interactions between 2,4,6-trinitrotoluene (TNT) and 2,4,6,8,10,12-hexanitro-2,4,6,8,10,12-hexaazaisowurtzitane (CL-20) and between 1,3,5,7-tetranitro-1,3,5,7-tetrazocane (HMX) and CL-20 were studied using calculated two-dimensional infrared (2D IR) spectra and the independent gradient model based on the Hirshfeld partition (IGMH) method, respectively. Based on the comparison of the theoretical infrared spectra and optimized geometries with experimental results, the theoretical models can effectively reproduce the experimental geometries. By analyzing cross-peaks in the 2D IR spectra of TNT/CL-20, the intermolecular vibrational energy transfer process between TNT and CL-20 was calculated, and the conclusion was made that the vibrational energy transfer process between CL-20 and TNTII (TNTIII) is relatively slower than between CL-20 and TNTI. As the vibration energy transfer is the bridge of the intermolecular interactions, the weak intermolecular interactions were visualized using the IGMH method, and the results demonstrate that the intermolecular non-covalent interactions of TNT/CL-20 include van der Waals (vdW) interactions and hydrogen bonds, while the intermolecular non-covalent interactions of HMX/CL-20 are mainly comprised of vdW interactions. Further, we determined that the intermolecular interaction can stabilize the trigger bond in TNT/CL-20 and HMX/CL-20 based on Mayer bond order density, and stronger intermolecular interactions generally indicate lower impact sensitivity of energetic materials. We believe that the results obtained in this work are important for a better understanding of the cocrystal mechanism and its application in the field of energetic materials.
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http://dx.doi.org/10.3390/molecules27072153DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9000797PMC
March 2022

Crystal structure of Acetyl-CoA carboxylase (AccB) from Streptomyces antibioticus and insights into the substrate-binding through in silico mutagenesis and biophysical investigations.

Comput Biol Med 2022 06 23;145:105439. Epub 2022 Mar 23.

State Key Laboratory of Microbial Metabolism, School of Life Sciences and Biotechnology, Shanghai Jiao Tong University, Shanghai, 200240, PR China; Joint International Research Laboratory of Metabolic & Developmental Sciences, Shanghai Jiao Tong University, Shanghai, PR China. Electronic address:

Acetyl-CoA carboxylase (ACC) is crucial for polyketides biosynthesis and acts as an essential metabolic checkpoint. It is also an attractive drug target against obesity, cancer, microbial infections, and diabetes. However, the lack of knowledge, particularly sequence-structure function relationship to narrate ligand-enzyme binding, has hindered the progress of ACC-specific therapeutics and unnatural "natural" polyketides. Structural characterization of such enzymes will boost the opportunity to understand the substrate binding, designing new inhibitors and information regarding the molecular rules which control the substrate specificity of ACCs. To understand the substrate specificity, we determined the crystal structure of AccB (Carboxyl-transferase, CT) from Streptomyces antibioticus with a resolution of 2.3 Å and molecular modeling approaches were employed to unveil the molecular mechanism of acetyl-CoA recognition and processing. The CT domain of S. antibioticus shares a similar structural organization with the previous structures and the two steps reaction was confirmed by enzymatic assay. Furthermore, to reveal the key hotspots required for the substrate recognition and processing, in silico mutagenesis validated only three key residues (V223, Q346, and Q514) that help in the fixation of the substrate. Moreover, we also presented atomic level knowledge on the mechanism of the substrate binding, which unveiled the terminal loop (500-514) function as an opening and closing switch and pushes the substrate inside the cavity for stable binding. A significant decline in the hydrogen bonding half-life was observed upon the alanine substitution. Consequently, the presented structural data highlighted the potential key interacting residues for substrate recognition and will also help to re-design ACCs active site for proficient substrate specificity to produce diverse polyketides.
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http://dx.doi.org/10.1016/j.compbiomed.2022.105439DOI Listing
June 2022

Evaluation of the Whole Proteome of to Identify Vaccine Targets for mRNA and Peptides-Based Vaccine Designing Against the Emerging Respiratory and Lung Cancer-Causing Bacteria.

Front Med (Lausanne) 2021 4;8:825876. Epub 2022 Feb 4.

Department of Bioinformatics and Biological Statistics, School of Life Sciences and Biotechnology, Shanghai Jiao Tong University, Shanghai, China.

is a rod-shaped Gram-negative bacterium linked with causing several infections which mostly includes hematological malignancies. It has been recently reported to be associated with the development and progression of lung cancer and is an emerging respiratory disease-causing bacterium. The treatment of individuals infected with bacteremia is difficult due to the fact that this pathogen has both intrinsic and acquired resistance mechanisms, typically resulting in a phenotype of multidrug resistance (MDR). Efforts are needed to design effective therapeutic strategies to curtail the emergence of this bacterium. Computational vaccine designing has proven its effectiveness, specificity, safety, and stability compared to conventional approaches of vaccine development. Therefore, the whole proteome of was screened for the characterization of potential vaccine targets through subtractive proteomics pipeline for therapeutics design. Annotation of the whole proteome confirmed the three immunogenic vaccine targets, such as (E3HHR6), (E3HH04), and (E3HWA2), which were used to map the putative immune epitopes. The shortlisted epitopes, specific against Cytotoxic T Lymphocytes, Helper T-cell Lymphocytes, and linear B-Cell, were used to design the mRNA and multi-epitopes vaccine (MEVC). Initial validations confirmed the antigenic and non-allergenic properties of these constructs, followed by docking with the immune receptor, TLR-5, which resulted in robust interactions. The interaction pattern that followed in the docking complex included formation of 5 hydrogen bonds, 2 salt bridges, and 165 non-bonded contacts. This stronger binding affinity was also assessed through using the mmGBSA approach, showing a total of free binding energy of -34.64 kcal/mol. Further validations based on cloning revealed a CAI score of 0.98 and an optimal percentage of GC contents (54.4%) indicated a putatively higher expression of the vaccine construct in . Moreover, immune simulation revealed strong antibodies production upon the injection of the designed MEVC that resulted in the highest peaks of IgM+ IgG production (>3,500) between 10 and 15 days. In conclusion the current study provide basis for vaccine designing against the emerging , which demands further experimental studies for and validations.
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http://dx.doi.org/10.3389/fmed.2021.825876DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8854494PMC
February 2022

SVPath: an accurate pipeline for predicting the pathogenicity of human exon structural variants.

Brief Bioinform 2022 03;23(2)

College of Computer Science and Electronic Engineering, Hunan University, Changsha, China.

Although there are a large number of structural variations in the chromosomes of each individual, there is a lack of more accurate methods for identifying clinical pathogenic variants. Here, we proposed SVPath, a machine learning-based method to predict the pathogenicity of deletions, insertions and duplications structural variations that occur in exons. We constructed three types of annotation features for each structural variation event in the ClinVar database. First, we treated complex structural variations as multiple consecutive single nucleotide polymorphisms events, and annotated them with correlation scores based on single nucleic acid substitutions, such as the impact on protein function. Second, we determined which genes the variation occurred in, and constructed gene-based annotation features for each structural variation. Third, we also calculated related features based on the transcriptome, such as histone signal, the overlap ratio of variation and genomic element definitions, etc. Finally, we employed a gradient boosting decision tree machine learning method, and used the deletions, insertions and duplications in the ClinVar database to train a structural variation pathogenicity prediction model SVPath. These structural variations are clearly indicated as pathogenic or benign. Experimental results show that our SVPath has achieved excellent predictive performance and outperforms existing state-of-the-art tools. SVPath is very promising in evaluating the clinical pathogenicity of structural variants. SVPath can be used in clinical research to predict the clinical significance of unknown pathogenicity and new structural variation, so as to explore the relationship between diseases and structural variations in a computational way.
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http://dx.doi.org/10.1093/bib/bbac014DOI Listing
March 2022

Evaluation and identification of essential therapeutic proteins and vaccinomics approach towards multi-epitopes vaccine designing against Legionella pneumophila for immune response instigation.

Comput Biol Med 2022 Feb 6;143:105291. Epub 2022 Feb 6.

Department of Bioinformatics and Biological Statistics, School of Life Sciences and Biotechnology, Shanghai Jiao Tong University, Shanghai, 200240, PR China; State Key Laboratory of Microbial Metabolism, Shanghai-Islamabad-Belgrade Joint Innovation Center on Antibacterial Resistances, Joint Laboratory of International Cooperation in Metabolic and Developmental Sciences, Ministry of Education and School of Life Sciences and Biotechnology, Shanghai Jiao Tong University, Shanghai, 200030, PR China; Peng Cheng Laboratory, Vanke Cloud City Phase I Building 8, Xili Street, Nashan District, Shenzhen, Guangdong, 518055, PR China. Electronic address:

The Legionellaceae group comprises the Legionella, containing 58 species with 70 serotypes. For instance, Legionella pneumophila is the deadliest serotype to cause Legionnaires infectious and is responsible for 90% of the infections in humans. The bacterial pathogen is associated with a severe lung infection, known as legionaries' disease. It is resistant to multiple drugs, thus warranting novel vaccine candidates identification to immune the host against infections caused by the said pathogen. For this, we applied the subtractive proteomics and reverse vaccinology approaches to annotate the most essential genes suitable for vaccine designing. From the whole proteome, only five proteins (Q5ZVG4, Q5ZRZ1, Q5ZWE6, Q5ZT09, and Q5ZUZ8) as the best targets for further processing as they fulfill all the standard parameters set for in silico vaccine design. Immuno-informatics approaches were further applied to the selected protein sequences to prioritized antigenic epitopes for design a multi-epitope subunit vaccine. A multi-epitopes vaccine was designed by using suitable linkers to link the CTL (cytotoxic T lymphocytes), HTL (Helper T lymphocytes), B cell epitopes, and adjuvant to strengthen the vaccine's immunogenicity. The MEVC(multi-epitopes vaccine construct) was reported to interact with human immune receptor TLR-2 (toll-like receptor) robustly (docking score = -357.18 kcal/mol), and a higher expression was achieved in the Escherichia coli system (CAI = 0.88, and GC contents = 54.34%). Moreover, immune simulation revealed that on the 3rd day, the neutralization of the antigen started, while on the 5th day, the antigen was completely neutralized by the secreted immune factors. In conclusion, the designed vaccine candidate effectively triggered the immune response against eh pathogen; however, wet lab-based experimentations are highly recommended to prove the protective immunological proficiency of the vaccine against L. pneumophila.
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http://dx.doi.org/10.1016/j.compbiomed.2022.105291DOI Listing
February 2022

Computational prediction of the effect of mutations in the receptor-binding domain on the interaction between SARS-CoV-2 and human ACE2.

Mol Divers 2022 Feb 9. Epub 2022 Feb 9.

Department of Biology, Faculty of Mathematics and Natural Sciences, Sam Ratulangi University, Manado, North Sulawesi, 95115, Indonesia.

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causing COVID-19 continues to mutate. Numerous studies have indicated that this viral mutation, particularly in the receptor-binding domain area, may increase the viral affinity for human angiotensin-converting enzyme 2 (hACE2), the receptor for viral entry into host cells, thereby increasing viral virulence and transmission. In this study, we investigated the binding affinity of SARS-CoV-2 variants (Delta plus, Iota, Kappa, Mu, Lambda, and C.1.2) on hACE2 using computational modeling with a protein-protein docking approach. The simulation results indicated that there were differences in the interactions between the RBD and hACE2, including hydrogen bonding, salt bridge interactions, non-bonded interactions, and binding free energy differences among these variants. Molecular dynamics simulations revealed that mutations in the RBD increase the stability of the hACE2-spike protein complex relative to the wild type, following the global stability trend and increasing the binding affinity. The value of binding-free energy calculated using molecular mechanics/Poisson-Boltzmann surface area (MM/PBSA) indicated that all mutations in the spike protein increased the contagiousness of SARS-CoV-2 variants. The findings of this study provide a foundation for developing effective interventions against these variants. Computational modeling elucidates that the spike protein of SARS-CoV-2 variants binds considerably stronger than the wild-type to hACE2.
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http://dx.doi.org/10.1007/s11030-022-10392-xDOI Listing
February 2022

Revealing the Relationship between Electric Fields and the Conformation of Oxytocin Using Quasi-Static Amide-I Two-Dimensional Infrared Spectra.

ACS Omega 2022 Feb 19;7(4):3758-3767. Epub 2022 Jan 19.

National Key Laboratory for Shock Wave and Detonation Physics Research, Institute of Fluid Physics, Chinese Academy of Engineering Physics, Mianyang 621900, China.

It is reported that the cis/trans conformation change of the peptide hormone oxytocin plays an important role in its receptors and activation and the cis conformation does not lead to antagonistic activity. Motivated by recent experiments and theories, the quasi-static amide-I 2D IR spectra of oxytocin are investigated using DFT/B3LYP (D3)/6-31G (d, p) in combination with the isotope labeling method under different electric fields. The theoretical amide-I IR spectra and bond length of the disulfide bond are consistent with the experimental values, which indicates that the theoretical modes are reasonable. Our theoretical results demonstrate that the oxytocin conformation is transformed from the cis conformation to the trans conformation with the change of the direction of the electric field, which is confirmed by the distance of the backbone carbonyl oxygen of Cys6 and Pro7, the Ramachandran plot of Cys6 and Pro7, the dihedral angle of C-S-S-C, and the rmsd of the oxytocin backbone. Moreover, the trans conformation as the result of the turn in the vicinity of Pro7 has a tighter secondary spatial structure than the cis conformation, including stronger hydrogen bonds, longer γ-turn geometry involving five amino acids, and a more stable disulfide bond. Our work provides new insights into the relationship between the conformation, the activation of the peptide hormone oxytocin, and the electric fields.
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http://dx.doi.org/10.1021/acsomega.1c06600DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8811763PMC
February 2022

Discovering potent inhibitors against the Mpro of the SARS-CoV-2. A medicinal chemistry approach.

Comput Biol Med 2022 Jan 26;143:105235. Epub 2022 Jan 26.

Department of Bioinformatics and Biological Statistics, School of Life Sciences and Biotechnology, Shanghai Jiao Tong University, Shanghai, 200240, PR China; Peng Cheng Laboratory, Shenzhen, Guangdong, 518055, China. Electronic address:

The global pandemic caused by a single-stranded RNA (ssRNA) virus known as the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is still at its peak, with new cases being reported daily. Although the vaccines have been administered on a massive scale, the frequent mutations in the viral gene and resilience of the future strains could be more problematic. Therefore, new compounds are always needed to be available for therapeutic approaches. We carried out the present study to discover potential drug compounds against the SARS-CoV-2 main protease (Mpro). A total of 16,000 drug-like small molecules from the ChemBridge database were virtually screened to obtain the top hits. As a result, 1032 hits were selected based on their docking scores. Next, these structures were prepared for molecular docking, and each small molecule was docked into the active site of the Mpro. Only compounds with solid interactions with the active site residues and the highest docking score were subjected to molecular dynamics (MD) simulation. The post-simulation analyses were carried out using the in-built GROMACS tools to gauge the stability, flexibility, and compactness. Principal component analysis (PCA) and hydrogen bonding were also calculated to observe trends and affinity of the drugs towards the target. Among the five top compounds, C1, C3, and C6 revealed strong interaction with the target's active site and remained highly stable throughout the simulation. We believe the predicted compounds in this study could be potential inhibitors in the natural system and can be utilized in designing therapeutic strategies against the SARS-CoV-2.
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http://dx.doi.org/10.1016/j.compbiomed.2022.105235DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8789387PMC
January 2022

The Omicron (B.1.1.529) variant of SARS-CoV-2 binds to the hACE2 receptor more strongly and escapes the antibody response: Insights from structural and simulation data.

Int J Biol Macromol 2022 Mar 19;200:438-448. Epub 2022 Jan 19.

Department of Bioinformatics and Biological Statistics, School of Life Sciences and Biotechnology, Shanghai Jiao Tong University, Shanghai 200240, PR China; State Key Laboratory of Microbial Metabolism, Shanghai-Islamabad-Belgrade Joint Innovation Center on Antibacterial Resistances, Joint Laboratory of International Laboratory of Metabolic and Developmental Sciences, Ministry of Education and School of Life Sciences and Biotechnology, Shanghai Jiao Tong University, Shanghai 200030, PR China; Peng Cheng Laboratory, Vanke Cloud City Phase I Building 8, Xili Street, Nashan District, Shenzhen, Guangdong 518055, PR China. Electronic address:

As SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2) continues to inflict chaos globally, a new variant officially known as B.1.1.529 was reported in South Africa and was found to harbor 30 mutations in the spike protein. It is too early to speculate on transmission and hospitalizations. Hence, more analyses are required, particularly to connect the genomic patterns to the phenotypic attributes to reveal the binding differences and antibody response for this variant, which can then be used for therapeutic interventions. Given the urgency of the required analysis and data on the B.1.1.529 variant, we have performed a detailed investigation to provide an understanding of the impact of these novel mutations on the structure, function, and binding of RBD to hACE2 and mAb to the NTD of the spike protein. The differences in the binding pattern between the wild type and B.1.1.529 variant complexes revealed that the key substitutions Asn417, Ser446, Arg493, and Arg498 in the B.1.1.529 RBD caused additional interactions with hACE2 and the loss of key residues in the B.1.1.529 NTD resulted in decreased interactions with three CDR regions (1-3) in the mAb. Further investigation revealed that B.1.1.529 displayed a stable dynamic that follows a global stability trend. In addition, the dissociation constant (K), hydrogen bonding analysis, and binding free energy calculations further validated the findings. Hydrogen bonding analysis demonstrated that significant hydrogen bonding reprogramming took place, which revealed key differences in the binding. The total binding free energy using MM/GBSA and MM/PBSA further validated the docking results and demonstrated significant variations in the binding. This study is the first to provide a basis for the higher infectivity of the new SARS-CoV-2 variants and provides a strong impetus for the development of novel drugs against them.
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http://dx.doi.org/10.1016/j.ijbiomac.2022.01.059DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8767976PMC
March 2022

Computational Chemistry in the Fight Against SARS-CoV-2.

Comb Chem High Throughput Screen 2022 Jan 11. Epub 2022 Jan 11.

Laboratory of Structural Bioinformatics, State Key Lab of Microbial Metabolism, Department of Bioinformatics & Biostatistics, School of life Sciences & Biotechnology, Shanghai Jiao Tong University, Shanghai, China.

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http://dx.doi.org/10.2174/1386207325666220111112656DOI Listing
January 2022

Core-Proteomics-Based Annotation of Antigenic Targets and Reverse-Vaccinology-Assisted Design of Ensemble Immunogen against the Emerging Nosocomial Infection-Causing Bacterium .

Int J Environ Res Public Health 2021 12 24;19(1). Epub 2021 Dec 24.

Department of Bioinformatics and Biological Statistics, School of Life Sciences and Biotechnology, Shanghai Jiao Tong University, Shanghai 200240, China.

is a ubiquitous Gram-negative emerging pathogen that causes hospital-acquired infection in both immunocompromised and immunocompetent patients. It is a multi-drug-resistant bacterium; therefore, an effective subunit immunogenic candidate is of great interest to encounter the pathogenesis of this pathogen. A protein-wide annotation of immunogenic targets was performed to fast-track the vaccine development against this pathogen, and structural-vaccinology-assisted epitopes were predicted. Among the total proteins, only three, A0A1T3FLU2, A0A1T3INK9, and A0A1V3U124, were shortlisted, which are the essential vaccine targets and were subjected to immune epitope mapping. The linkers EAAK, AAY, and GPGPG were used to link CTL, HTL, and B-cell epitopes and an adjuvant was also added at the N-terminal to design a multi-epitope immunogenic construct (MEIC). The computationally predicted physiochemical properties of the ensemble immunogen reported a highly antigenic nature and produced multiple interactions with immune receptors. In addition, the molecular dynamics simulation confirmed stable binding and good dynamic properties. Furthermore, the computationally modeled immune response proposed that the immunogen triggered a strong immune response after several doses at different intervals. Neutralization of the antigen was observed on the 3rd day of injection. Conclusively, the immunogenic construct produces protection against ; however, further immunological testing is needed to unveil its real efficacy.
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http://dx.doi.org/10.3390/ijerph19010194DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8750920PMC
December 2021

Computational modelling of potentially emerging SARS-CoV-2 spike protein RBDs mutations with higher binding affinity towards ACE2: A structural modelling study.

Comput Biol Med 2022 02 30;141:105163. Epub 2021 Dec 30.

Department of Bioinformatics and Biological Statistics, School of Life Sciences and Biotechnology, Shanghai Jiao Tong University, Shanghai, 200240, PR China; Peng Cheng Laboratory, Vanke Cloud City Phase I Building 8, Xili Street, Nashan District, Shenzhen, Guangdong, 518055, PR China; State Key Laboratory of Microbial Metabolism, Shanghai-Islamabad-Belgrade Joint Innovation Center on Antibacterial Resistances, Joint Laboratory of International Cooperation in Metabolic and Developmental Sciences, Ministry of Education and School of Life Sciences and Biotechnology, Shanghai Jiao Tong University, Shanghai, 200030, PR China. Electronic address:

The spike protein of SARS-CoV-2 and the host ACE2 receptor plays a vital role in the entry to the cell. Among which the hotspot residue 501 is continuously subjected to positive selection pressure and induces unusual virulence. Keeping in view the importance of the hot spot residue 501, we predicted the potentially emerging structural variants of 501 residue. We analyzed the binding pattern of wild type and mutants (Spike RBD) to the ACE2 receptor by deciphering variations in the amino acids' interaction networks by graph kernels along with evolutionary, network metrics, and energetic information. Our analysis revealed that N501I, N501T, and N501V increase the binding affinity and alter the intra and inter-residue bonding networks. The N501T has shown strong positive selection and fitness in other animals. Docking results and repeated simulations (three times) confirmed the structural stability and tighter binding of these three variants, correlated with the previous results following the global stability trend. Consequently, we reported three variants N501I, N501T, and N501V could worsen the situation further if they emerged. The relations between the viral fitness and binding affinity is a complicated game thus the emergence of high affinity mutations in the SARS-CoV-2 RBD brings up the question of whether or not positive selection favours these mutations or not?
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http://dx.doi.org/10.1016/j.compbiomed.2021.105163DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8716154PMC
February 2022

Comparative mutational analysis of SARS-CoV-2 isolates from Pakistan and structural-functional implications using computational modelling and simulation approaches.

Comput Biol Med 2022 02 25;141:105170. Epub 2021 Dec 25.

Department of Bioinformatics and Biological Statistics, School of Life Sciences and Biotechnology, Shanghai Jiao Tong University, Shanghai, 200240, PR China; State Key Laboratory of Microbial Metabolism, Shanghai-Islamabad-Belgrade Joint Innovation Center on Antibacterial Resistances, Joint Laboratory of International Laboratory of Metabolic and Developmental Sciences, Ministry of Education and School of Life Sciences and Biotechnology, Shanghai Jiao Tong University, Shanghai, 200030, PR China; Peng Cheng Laboratory, Vanke Cloud City Phase I Building 8, Xili Street, Nashan District, Shenzhen, Guangdong, 518055, PR China. Electronic address:

SARS-CoV-2, an RNA virus, has been prone to high mutations since its first emergence in Wuhan, China, and throughout its spread. Its genome has been sequenced continuously by many countries, including Pakistan, but the results vary. Understanding its genomic patterns and connecting them with phenotypic features will help in devising therapeutic strategies. Thus, in this study, we explored the mutation landscape of 250 Pakistani isolates of SARS-CoV-2 genomes to check the genome diversity and examine the impact of these mutations on protein stability and viral pathogenesis in comparison with a reference sequence (Wuhan NC 045512.2). Our results revealed that structural proteins mainly exhibit more mutations than others in the Pakistani isolates; in particular, the nucleocapsid protein is highly mutated. In comparison, the spike protein is the most mutated protein globally. Furthermore, nsp12 was found to be the most mutated NSP in the Pakistani isolates and worldwide. Regarding accessory proteins, ORF3A is the most mutated in the Pakistani isolates, whereas ORF8 is highly mutated in world isolates. These mutations decrease the structural stability of their proteins and alter different biological pathways. Molecular docking, the dissociation constant (K), and MM/GBSA analysis showed that mutations in the S protein alter its binding with ACE2. The spike protein mutations D614G-S943T-V622F (-75.17 kcal/mol), D614G-Q677H (-75.78 kcal/mol), and N74K-D614G (-73.84 kcal/mol) exhibit stronger binding energy than the wild type (-66.34 kcal/mol), thus increasing infectivity. Furthermore, the simulation results strongly corroborated the predicted protein servers. Our analysis findings also showed that E, M, ORF6, ORF7A, ORF7B, and ORF10 are the most stable coding genes; they may be suitable targets for vaccine and drug development.
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http://dx.doi.org/10.1016/j.compbiomed.2021.105170DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8709794PMC
February 2022

Computational Methods for Structure-Based Drug Design Through System Biology.

Methods Mol Biol 2022 ;2385:161-174

State Key Laboratory of Microbial Metabolism, Shanghai-Islamabad-Belgrade Joint Innovation Center on Antibacterial Resistances, Joint International Research Laboratory of Metabolic & Developmental Sciences and School of Life Sciences and Biotechnology, Shanghai Jiao Tong University, Shanghai, People's Republic of China.

The advances in computational chemistry and biology, computer science, structural biology, and molecular biology go in parallel with the rapid progress in target-based systems. This technique has become a powerful tool in medicinal chemistry for the identification of hit molecules. The recent developments in target-based systems have played a major role in the creation of libraries of compounds, and it has also been widely applied for the design of molecular docking methods. The main advantage of this method is that it hits the fragment that has the strongest binding, has relatively small size, and leads to better compounds in terms of pharmacokinetic properties when compared with virtual screening (VS) and high-throughput screening (HTS) hits. De novo design is an essential aspect of target-based systems and requires the synthesis of chemical to allow the design of promising compound.
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http://dx.doi.org/10.1007/978-1-0716-1767-0_9DOI Listing
January 2022
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