Publications by authors named "Junmei Wang"

242 Publications

Constructing Zn-P charge transfer bridge over ZnFeO-black phosphorus 3D microcavity structure: Efficient photocatalyst design in visible-near-infrared region.

J Colloid Interface Sci 2021 May 12;600:463-472. Epub 2021 May 12.

School of Material Science and Engineering, Jiangsu University of Science and Technology, Zhenjiang 212003, China. Electronic address:

Black phosphorus (BP) is one of the most promising visible-near-infrared light-driven photocatalysts with favorite photoelectric properties and unique tunable direct band gap. Nevertheless, the further development of BP is hindered by the fast carrier recombination rate and high Gibbs free energy. Herein, an innovative strategy is developed for the controllable construction of Zn-P bonds induced zinc ferrite/black phosphorus (ZnFeO-BP) three dimensions (3D) microcavity structure. The Zn-P bonds serve as an efficient channel to optimize the carrier transport and Gibbs free energy of BP simultaneously. Besides, the unique 3D core-shell microcavity structure maintains the multiple reflections of sunlight inside the catalysts, which greatly improves the sunlight utilization upon photocatalysis. An optimized photocatalytic hydrogen production rate of 560 µmol hg under near-infrared light (>820 nm) is achieved. A possible photocatalytic mechanism is proposed based on a series of experimental characterizations and theoretical calculations, this work provides a new sight to design high-quantity BP-based full-spectrum photocatalysts for solar energy conversion.
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http://dx.doi.org/10.1016/j.jcis.2021.05.043DOI Listing
May 2021

Hypoxia acts as an environmental cue for the human tissue-resident memory T cell differentiation program.

JCI Insight 2021 May 24;6(10). Epub 2021 May 24.

Department of Melanoma Medical Oncology, University of Texas (UT) MD Anderson Cancer Center, Houston, Texas, USA.

Tissue-resident memory T cells (TRM) provide frontline defense against infectious diseases and contribute to antitumor immunity; however, aside from the necessity of TGF-β, knowledge regarding TRM-inductive cues remains incomplete, particularly for human cells. Oxygen tension is an environmental cue that distinguishes peripheral tissues from the circulation, and here, we demonstrate that differentiation of human CD8+ T cells in the presence of hypoxia and TGF-β1 led to the development of a TRM phenotype, characterized by a greater than 5-fold increase in CD69+CD103+ cells expressing human TRM hallmarks and enrichment for endogenous human TRM gene signatures, including increased adhesion molecule expression and decreased expression of genes involved in recirculation. Hypoxia and TGF-β1 synergized to produce a significantly larger population of TRM phenotype cells than either condition alone, and comparison of these cells from the individual and combination conditions revealed distinct phenotypic and transcriptional profiles, indicating a programming response to milieu rather than a mere expansion. Our findings identify a likely previously unreported cue for the TRM differentiation program and can enable facile generation of human TRM phenotype cells in vitro for basic studies and translational applications such as adoptive cellular therapy.
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http://dx.doi.org/10.1172/jci.insight.138970DOI Listing
May 2021

VAD-MM/GBSA: A Variable Atomic Dielectric MM/GBSA Model for Improved Accuracy in Protein-Ligand Binding Free Energy Calculations.

J Chem Inf Model 2021 May 20. Epub 2021 May 20.

Innovation Institute for Artificial Intelligence in Medicine, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, Zhejiang 310058, China.

The molecular mechanics/generalized Born surface area (MM/GBSA) has been widely used in end-point binding free energy prediction in structure-based drug design (SBDD). However, in practice, it is usually being treated as a disputed method mostly because of its system dependence. Here, combining with machine-learning optimization, we developed a novel version of MM/GBSA, named variable atomic dielectric MM/GBSA (VAD-MM/GBSA), by assigning variable dielectric constants directly to the protein/ligand atoms. The new strategy exhibits markedly improved accuracy in binding affinity calculations for various protein-ligand systems and is promising to be used in the postprocessing of structure-based virtual screening. Moreover, VAD-MM/GBSA outperformed prime MM/GBSA in Schrödinger software and showed remarkable predictive performance for specific protein targets, such as POL polyprotein, human immunodeficiency virus type 1 (HIV-1) protease, etc. Our study showed that the VAD-MM/GBSA method with little extra computational overhead provides a potential replacement of the MM/GBSA in AMBER software. An online web server of VAD-MMGBSA has been developed and is now available at http://cadd.zju.edu.cn/vdgb.
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http://dx.doi.org/10.1021/acs.jcim.1c00091DOI Listing
May 2021

In silico binding profile characterization of SARS-CoV-2 spike protein and its mutants bound to human ACE2 receptor.

Brief Bioinform 2021 May 19. Epub 2021 May 19.

Department of Pharmaceutical Sciences and Computational Chemical Genomics Screening Center, School of Pharmacy, University of Pittsburgh, Pittsburgh, PA 15261, USA.

Severe acute respiratory syndrome coronavirus (SARS-CoV-2), a novel coronavirus, has brought an unprecedented pandemic to the world and affected over 64 million people. The virus infects human using its spike glycoprotein mediated by a crucial area, receptor-binding domain (RBD), to bind to the human ACE2 (hACE2) receptor. Mutations on RBD have been observed in different countries and classified into nine types: A435S, D364Y, G476S, N354D/D364Y, R408I, V341I, V367F, V483A and W436R. Employing molecular dynamics (MD) simulation, we investigated dynamics and structures of the complexes of the prototype and mutant types of SARS-CoV-2 spike RBDs and hACE2. We then probed binding free energies of the prototype and mutant types of RBD with hACE2 protein by using an end-point molecular mechanics Poisson Boltzmann surface area (MM-PBSA) method. According to the result of MM-PBSA binding free energy calculations, we found that V367F and N354D/D364Y mutant types showed enhanced binding affinities with hACE2 compared to the prototype. Our computational protocols were validated by the successful prediction of relative binding free energies between prototype and three mutants: N354D/D364Y, V367F and W436R. Thus, this study provides a reliable computational protocol to fast assess the existing and emerging RBD mutations. More importantly, the binding hotspots identified by using the molecular mechanics generalized Born surface area (MM-GBSA) free energy decomposition approach can guide the rational design of small molecule drugs or vaccines free of drug resistance, to interfere with or eradicate spike-hACE2 binding.
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http://dx.doi.org/10.1093/bib/bbab188DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8194596PMC
May 2021

Identification of QTL for barley grain size.

PeerJ 2021 29;9:e11287. Epub 2021 Apr 29.

Tasmanian Institute of Agriculture, University of Tasmania, Prospect, TAS, Australia.

Background: Barley grain size is one of the key factors determining storage capacity during grain filling. Large, well-filled grains also have a high malt extract potential. Grain size is a complex quantitative trait and can be easily affected by environmental factors thus the identification of genes controlling the trait and the use of molecular markers linked to the genes in breeding program is the most effective way of improving grain size.

Methods: Grain sizes of 188 doubled-haploid (DH) lines derived from the cross of a Japanese malting barley variety (Naso Nijo) and a Chinese feed barley variety (TX9425) were obtained from three different sites in two consecutive years. The average data were used for identifying QTL for grain size.

Results: A total of four significant QTL were identified for grain length (GL) and three for grain width (GW). The two major GL QTL are located at similar positions to the QTL for malt extract on 2H and gene on 3H, respectively. However, the GL QTL on 2H is more likely a different one from the malt extract QTL as most of the candidate genes are located outside the fine mapped QTL region for malt extract. The GL QTL on 3H is closely linked with gene but not due to a pleiotropic effect of . The three QTL for grain width on 1H, 2H and 5H, respectively, were located at same position to those for GL.
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http://dx.doi.org/10.7717/peerj.11287DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8088763PMC
April 2021

Drug-Drug Interaction Between Oxycodone and Diazepam by a Combined Pharmacokinetic and Pharmacodynamic Modeling Approach.

ACS Chem Neurosci 2021 05 5;12(10):1777-1790. Epub 2021 May 5.

Department of Pharmaceutical Sciences and Computational Chemical Genomics Screening Center, School of Pharmacy, The University of Pittsburgh, 3501 Terrace Street, Pittsburgh, Pennsylvania 15261, United States.

Opioids and benzodiazepines have complex drug-drug interactions (DDIs), which serve as an important source of adverse drug effects. In this work, we predicted the DDI between oxycodone (OXY) and diazepam (DZP) in the human body by applying pharmacokinetic (PK) and pharmacodynamic (PD) modeling and simulation. First, we studied the PK interaction between OXY and DZP with a physiologically based pharmacokinetic (PBPK) model. Second, we applied molecular modeling techniques including molecular docking, molecular dynamics (MD) simulation, and the molecular mechanics/Poisson-Boltzmann surface area (MM-PBSA) free energy method to predict the PD-DDI between these two drugs. The PK interaction between OXY and DZP predicted by the PBPK model was not obvious. No significant interaction was observed between the two drugs at normal doses, though very high doses of DZP demonstrated a non-negligible inhibitory effect on OXY metabolism. On the contrary, the molecular modeling study shows that DZP has potential to compete with OXY at the same binding pocket of the active μ-opioid receptor (MOR) and κ-opioid receptor (KOR). MD simulation and MM-PBSA calculation results demonstrated that there is likely a synergetic effect between OXY and DZP binding to opioid receptors, as OXY is likely to target the active MOR while DZP selectively binds to the active KOR. Thus, pharmacokinetics contributes slightly to the DDI between OXY and DZP although an overdose of DZP has been brought to attention. Pharmacodynamics is likely to play a more important role than pharmacokinetics in revealing the mechanism of DDI between OXY and DZP.
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http://dx.doi.org/10.1021/acschemneuro.0c00810DOI Listing
May 2021

Identification and characterization of HAK/KUP/KT potassium transporter gene family in barley and their expression under abiotic stress.

BMC Genomics 2021 May 1;22(1):317. Epub 2021 May 1.

Institute of Crop Science, Zhejiang University, Hangzhou, 310058, China.

Background: HAK/KUP/KT (High-affinity K transporters/K uptake permeases/K transporters) is the largest potassium transporter family in plants, and plays pivotal roles in K uptake and transport, as well as biotic and abiotic stress responses. However, our understanding of the gene family in barley (Hordeum vulgare L.) is quite limited.

Results: In the present study, we identified 27 barley HAK/KUP/KT genes (hereafter called HvHAKs) through a genome-wide analysis. These HvHAKs were unevenly distributed on seven chromosomes, and could be phylogenetically classified into four clusters. All HvHAK protein sequences possessed the conserved motifs and domains. However, the substantial difference existed among HAK members in cis-acting elements and tissue expression patterns. Wheat had the most orthologous genes to barley HAKs, followed by Brachypodium distachyon, rice and maize. In addition, six barley HAK genes were selected to investigate their expression profiling in response to three abiotic stresses by qRT-PCR, and their expression levels were all up-regulated under salt, hyperosmotic and potassium deficiency treatments.

Conclusion: Twenty seven HAK genes (HvHAKs) were identified in barley, and they differ in tissue expression patterns and responses to salt stress, drought stress and potassium deficiency.
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http://dx.doi.org/10.1186/s12864-021-07633-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8088664PMC
May 2021

The distribution of Fusarium graminearum and F. asiaticum causing Fusarium head blight of wheat in relation to climate and cropping system.

Plant Dis 2021 Apr 21. Epub 2021 Apr 21.

Henan Academy of Agricultural SciencesZhengzhou , China, 450002;

In the main wheat production area of China (The Huang Huai Plain, HHP), both Fusarium graminearum and F. asiaticum, the causal agents of Fusarium head blight (FHB), are present. We investigated whether the relative prevalence of F. graminearum and F. asiaticum is related to cropping systems and/or climate factors. A total of 1844 Fusarium isolates were obtained from 103 fields of two cropping systems: maize-wheat and rice-wheat rotations. To maximize the differences in climatic conditions, isolates were sampled from the north and south HHP region. Based on the phylogenetic analysis of EF-1α and Tri101sequences, 1207 of the 1844 isolates belonged to F. graminearum, and the remaining 637 isolates belonged to F. asiaticum. The former was predominant in the northern region: 1022 of the 1078 Fusarium isolates in the north were F. graminearum. The latter was predominant in the southern region: 581 of the 766 Fusarium isolates belonging to F. asiaticum. Analysis based on generalised linear modelling, the relative prevalence of the two species was associated more with climatic conditions than with the cropping system. Fusarium graminearum was associated with drier conditions, cooler conditions during the winter but warmer conditions in the infection and grain-colonization period, and with the maize-wheat rotation. The opposite was true for F. asiaticum. Except 15-ADON, the trichothecene chemotype composition of F. asiaticum differed between the two cropping systems. The 3-ADON was more prevalent in the maize-wheat rotation; whereas NIV more prevalent in the rice-wheat rotation. The results also suggested that environmental conditions in the overwintering period appeared to be more important than that in the infection and grain-colonization and pre-anthesis sporulation periods in affecting the relative prevalence of F. graminearum and F. asiaticum. More research is needed to study the effect of overwintering conditions on subsequent epidemic in the following spring.
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http://dx.doi.org/10.1094/PDIS-01-21-0013-REDOI Listing
April 2021

Machine learning on ligand-residue interaction profiles to significantly improve binding affinity prediction.

Brief Bioinform 2021 Mar 24. Epub 2021 Mar 24.

Department of Pharmaceutical Sciences and Computational Chemical Genomics Screening Center, School of Pharmacy, University of Pittsburgh, Pittsburgh, PA 15261, USA.

Structure-based virtual screenings (SBVSs) play an important role in drug discovery projects. However, it is still a challenge to accurately predict the binding affinity of an arbitrary molecule binds to a drug target and prioritize top ligands from an SBVS. In this study, we developed a novel method, using ligand-residue interaction profiles (IPs) to construct machine learning (ML)-based prediction models, to significantly improve the screening performance in SBVSs. Such a kind of the prediction model is called an IP scoring function (IP-SF). We systematically investigated how to improve the performance of IP-SFs from many perspectives, including the sampling methods before interaction energy calculation and different ML algorithms. Using six drug targets with each having hundreds of known ligands, we conducted a critical evaluation on the developed IP-SFs. The IP-SFs employing a gradient boosting decision tree (GBDT) algorithm in conjunction with the MIN + GB simulation protocol achieved the best overall performance. Its scoring power, ranking power and screening power significantly outperformed the Glide SF. First, compared with Glide, the average values of mean absolute error and root mean square error of GBDT/MIN + GB decreased about 38 and 36%, respectively. Second, the mean values of squared correlation coefficient and predictive index increased about 225 and 73%, respectively. Third, more encouragingly, the average value of the areas under the curve of receiver operating characteristic for six targets by GBDT, 0.87, is significantly better than that by Glide, which is only 0.71. Thus, we expected IP-SFs to have broad and promising applications in SBVSs.
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http://dx.doi.org/10.1093/bib/bbab054DOI Listing
March 2021

Incorporating structural similarity into a scoring function to enhance the prediction of binding affinities.

J Cheminform 2021 Feb 15;13(1):11. Epub 2021 Feb 15.

Department of Pharmaceutical Sciences and Computational Chemical Genomics Screening Center, School of Pharmacy, University of Pittsburgh, Pittsburgh, PA, 15261, USA.

In this study, we developed a novel algorithm to improve the screening performance of an arbitrary docking scoring function by recalibrating the docking score of a query compound based on its structure similarity with a set of training compounds, while the extra computational cost is neglectable. Two popular docking methods, Glide and AutoDock Vina were adopted as the original scoring functions to be processed with our new algorithm and similar improvement performance was achieved. Predicted binding affinities were compared against experimental data from ChEMBL and DUD-E databases. 11 representative drug receptors from diverse drug target categories were applied to evaluate the hybrid scoring function. The effects of four different fingerprints (FP2, FP3, FP4, and MACCS) and the four different compound similarity effect (CSE) functions were explored. Encouragingly, the screening performance was significantly improved for all 11 drug targets especially when CSE = S (S is the Tanimoto structural similarity) and FP2 fingerprint were applied. The average predictive index (PI) values increased from 0.34 to 0.66 and 0.39 to 0.71 for the Glide and AutoDock vina scoring functions, respectively. To evaluate the performance of the calibration algorithm in drug lead identification, we also imposed an upper limit on the structural similarity to mimic the real scenario of screening diverse libraries for which query ligands are general-purpose screening compounds and they are not necessarily structurally similar to reference ligands. Encouragingly, we found our hybrid scoring function still outperformed the original docking scoring function. The hybrid scoring function was further evaluated using external datasets for two systems and we found the PI values increased from 0.24 to 0.46 and 0.14 to 0.42 for A2AR and CFX systems, respectively. In a conclusion, our calibration algorithm can significantly improve the virtual screening performance in both drug lead optimization and identification phases with neglectable computational cost.
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http://dx.doi.org/10.1186/s13321-021-00493-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7884591PMC
February 2021

Whole genome sequencing of skull-base chordoma reveals genomic alterations associated with recurrence and chordoma-specific survival.

Nat Commun 2021 02 3;12(1):757. Epub 2021 Feb 3.

Division of Cancer Epidemiology and Genetics, National Cancer Institute, NIH, DHHS, Bethesda, MD, USA.

Chordoma is a rare bone tumor with an unknown etiology and high recurrence rate. Here we conduct whole genome sequencing of 80 skull-base chordomas and identify PBRM1, a SWI/SNF (SWItch/Sucrose Non-Fermentable) complex subunit gene, as a significantly mutated driver gene. Genomic alterations in PBRM1 (12.5%) and homozygous deletions of the CDKN2A/2B locus are the most prevalent events. The combination of PBRM1 alterations and the chromosome 22q deletion, which involves another SWI/SNF gene (SMARCB1), shows strong associations with poor chordoma-specific survival (Hazard ratio [HR] = 10.55, 95% confidence interval [CI] = 2.81-39.64, p = 0.001) and recurrence-free survival (HR = 4.30, 95% CI = 2.34-7.91, p = 2.77 × 10). Despite the low mutation rate, extensive somatic copy number alterations frequently occur, most of which are clonal and showed highly concordant profiles between paired primary and recurrence/metastasis samples, indicating their importance in chordoma initiation. In this work, our findings provide important biological and clinical insights into skull-base chordoma.
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http://dx.doi.org/10.1038/s41467-021-21026-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7859411PMC
February 2021

Resection and survival data from a clinical trial of glioblastoma multiforme-specific IRDye800-BBN fluorescence-guided surgery.

Bioeng Transl Med 2021 Jan 31;6(1):e10182. Epub 2020 Aug 31.

Laboratory of Molecular Imaging and Nanomedicine (LOMIN) National Institute of Biomedical Imaging and Bioengineering (NIBIB), National Institutes of Health (NIH) Bethesda Maryland USA.

Supra-maximum surgical tumor resection without neurological damage is highly valuable for treatment and prognosis of patients with glioblastoma multiforme (GBM). We developed a GBM-specific fluorescence probe using IRDye800CW (peak absorption/emission, 778/795 nm) and bombesin (BBN), which (IRDye800-BBN) targets the gastrin-releasing peptide receptor, and evaluated the image-guided resection efficiency, sensitivity, specificity, and survivability. Twenty-nine patients with newly diagnosed GBM were enrolled. Sixteen hours preoperatively, IRDye800-BBN (1 mg in 20 ml sterile water) was intravenously administered. A customized fluorescence surgical navigation system was used intraoperatively. Postoperatively, enhanced magnetic resonance images were used to assess the residual tumor volume, calculate the resection extent, and confirm whether complete resection was achieved. Tumor tissues and nonfluorescent brain tissue in adjacent noneloquent boundary areas were harvested and assessed for diagnostic accuracy. Complete resection was achieved in 82.76% of patients. The median extent of resection was 100% (range, 90.6-100%). Eighty-nine samples were harvested, including 70 fluorescence-positive and 19 fluorescence-negative samples. The sensitivity and specificity of IRDye800-BBN were 94.44% (95% CI, 85.65-98.21%) and 88.24% (95% CI, 62.25-97.94%), respectively. Twenty-five patients were followed up (median, 13.5 [3.1-36.0] months), and 14 had died. The mean preoperative and immediate and 6-month postoperative Karnofsky performance scores were 77.9 ± 11.8, 71.3 ± 19.2, and 82.6 ± 14.7, respectively. The median overall and progression-free survival were 23.1 and 14.1 months, respectively. In conclusion, GBM-specific fluorescent IRDye800-BBN can help neurosurgeons identify the tumor boundary with sensitivity and specificity, and may improve survival outcomes.
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http://dx.doi.org/10.1002/btm2.10182DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7823121PMC
January 2021

Determination of van der Waals Parameters Using a Double Exponential Potential for Nonbonded Divalent Metal Cations in TIP3P Solvent.

J Chem Theory Comput 2021 Feb 27;17(2):1086-1097. Epub 2021 Jan 27.

Department of Pharmaceutical Sciences and Computational Chemical Genomics Screening Center, School of Pharmacy, University of Pittsburgh, Pittsburgh, Pennsylvania 15261, United States.

A double exponential (DE) functional form for Lennard-Jones (LJ) interactions, proposed in our previous study, has many advantages over LJ potentials including a natural softcore characteristic for the convenience of the pathway-based free-energy calculations, fast convergence, and flexibility in use. In this work, we put the first step on the application of the DE functional form by identifying a DE potential, coined DE-TIP3P, for molecular simulations using the TIP3P water model. The developed DE-TIP3 potential was better than LJ potential in reproducing the experimental water properties. Afterward, we developed the nonbonded models of 15 divalent metal ions, which frequently appear and play vital roles in biological systems, to be consistent with the DE-TIP3P potential and TIP3P water model. Our nonbonded models were as good as the complicated nonbonded dummy cationic models by Jiang et al. and the nonbonded 12-6-4 LJ models by Li and Merz in reproducing the experimental properties of those ions. Moreover, our nonbonded models achieved a better performance than the compromise (CM) LJ models and 12-6-4 LJ models, developed by Li and Merz, in reproducing the properties of MgCl in aqueous solution.
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http://dx.doi.org/10.1021/acs.jctc.0c01267DOI Listing
February 2021

ALeRT-COVID: Attentive Lockdown-awaRe Transfer Learning for Predicting COVID-19 Pandemics in Different Countries.

J Healthc Inform Res 2021 Jan 6:1-16. Epub 2021 Jan 6.

Cornell University, Ithaca, USA.

Countries across the world are in different stages of COVID-19 trajectory, among which many have implemented lockdown measures to prevent its spread. Although the lockdown is effective in such prevention, it may put the economy into a depression. Predicting the epidemic progression with the government switching the lockdown on or off is critical. We propose a transfer learning approach called ALeRT-COVID using attention-based recurrent neural network (RNN) architecture to predict the epidemic trends for different countries. A source model was trained on the pre-defined source countries and then transferred to each target country. The lockdown measure was introduced to our model as a predictor and the attention mechanism was utilized to learn the different contributions of the confirmed cases in the past days to the future trend. Results demonstrated that the transfer learning strategy is helpful especially for early-stage countries. By introducing the lockdown predictor and the attention mechanism, ALeRT-COVID showed a significant improvement in the prediction performance. We predicted the confirmed cases in 1 week when extending and easing lockdown separately. Our results show that lockdown measures are still necessary for several countries. We expect our research can help different countries to make better decisions on the lockdown measures.
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http://dx.doi.org/10.1007/s41666-020-00088-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7786857PMC
January 2021

Nonequilibrium molecular dynamics simulations of infrared laser-induced dissociation of a tetrameric Aβ42 β-barrel in a neuronal membrane model.

Chem Phys Lipids 2021 Jan 23;234:105030. Epub 2020 Dec 23.

CNRS, Université de Paris, UPR9080, Laboratoire de Biochimie Théorique, Paris, France; Institut de Biologie Physico-Chimique, Fondation Edmond de Rothschild, PSL Research University, Paris, France. Electronic address:

Experimental studies have reported that the amyloid-β proteins can form pores in cell membranes, and this could be one possible source of toxicity in Alzheimer's disease. Dissociation of these pores could therefore be a potential therapeutic approach. It is known that high photon density free-electron laser experiments and laser-induced nonequilibrium molecular dynamics simulations (NEMD) can dissociate amyloid fibrils at specific frequencies in vitro. Our question is whether NEMD simulations can dissociate amyloid pores in a bilayer mimicking a neuronal membrane, and as an example, we select a tetrameric Aβ42 β-barrel. Our simulations shows that the resonance between the laser field and the amide I vibrational mode of the barrel destabilises all intramolecular and intermolecular hydrogen bonds of Aβ42 and converts the β-barrel to a random/coil disordered oligomer. Starting from this disordered oligomer, extensive standard MD simulations shows sampling of disordered Aβ42 states without any increase of β-sheet and reports that the orientational order of lipids is minimally disturbed. Interestingly, the frequency to be employed to dissociate this beta-barrel is specific to the amino acid sequence. Taken together with our previous simulation results, this study indicates that infrared laser irradiation can dissociate amyloid fibrils and oligomers in bulk solution and in a membrane environment without affecting the surrounding molecules, offering therefore a promising way to retard the progression of AD.
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http://dx.doi.org/10.1016/j.chemphyslip.2020.105030DOI Listing
January 2021

Hierarchically porous hydrangea-like InS/InO heterostructures for enhanced photocatalytic hydrogen evolution.

J Colloid Interface Sci 2021 Apr 13;587:876-882. Epub 2020 Nov 13.

School of Engineering, Edith Cowan University, 270 Joondalup Drive, Joondalup, WA, 6027, Australia. Electronic address:

Semiconductor-based photocatalytic hydrogen evolution is considered to be a promising and cost-effective approach to address the environmental issues and energy crisis. It still remains a great challenge to design highly-efficient semiconductor photocatalysts via a facile method. Herein, hierarchically porous hydrangea-like InS/InO heterostructures are successfully synthesized via a simple in situ oxidization process. The formed InS/InO heterostructures exhibit superior photocatalytic activity to the counterpart InS and InO. The boosted photocatalytic performance is ascribed to the formed heterostructures, which greatly facilitate the interfacial charge transfer. Moreover, the formation of hierarchically porous heterostructures increases the number of active sites and improves the permeability, and thus significantly promotes the photocatalytic H evolution activity. This work may provide a new insight for designing InS-based heterostructures for efficient solar light conversion.
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http://dx.doi.org/10.1016/j.jcis.2020.11.048DOI Listing
April 2021

Transmembrane Polar Relay Drives the Allosteric Regulation for ABCG5/G8 Sterol Transporter.

Int J Mol Sci 2020 Nov 19;21(22). Epub 2020 Nov 19.

Department of Biochemistry, Microbiology and Immunology, Faculty of Medicine, University of Ottawa, Ottawa, ON K1H 8M5, Canada.

The heterodimeric ATP-binding cassette (ABC) sterol transporter, ABCG5/G8, is responsible for the biliary and transintestinal secretion of cholesterol and dietary plant sterols. Missense mutations of ABCG5/G8 can cause sitosterolemia, a loss-of-function disorder characterized by plant sterol accumulation and premature atherosclerosis. A new molecular framework was recently established by a crystal structure of human ABCG5/G8 and reveals a network of polar and charged amino acids in the core of the transmembrane domains, namely, a polar relay. In this study, we utilize genetic variants to dissect the mechanistic role of this transmembrane polar relay in controlling ABCG5/G8 function. We demonstrated a sterol-coupled ATPase activity of ABCG5/G8 by cholesteryl hemisuccinate (CHS), a relatively water-soluble cholesterol memetic, and characterized CHS-coupled ATPase activity of three loss-of-function missense variants, R543S, E146Q, and A540F, which are respectively within, in contact with, and distant from the polar relay. The results established an in vitro phenotype of the loss-of-function and missense mutations of ABCG5/G8, showing significantly impaired ATPase activity and loss of energy sufficient to weaken the signal transmission from the transmembrane domains. Our data provide a biochemical evidence underlying the importance of the polar relay and its network in regulating the catalytic activity of ABCG5/G8 sterol transporter.
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http://dx.doi.org/10.3390/ijms21228747DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7699580PMC
November 2020

How Well Does the Extended Linear Interaction Energy Method Perform in Accurate Binding Free Energy Calculations?

J Chem Inf Model 2020 12 19;60(12):6624-6633. Epub 2020 Nov 19.

Department of Pharmaceutical Sciences and Computational Chemical Genomics Screening Center, School of Pharmacy, University of Pittsburgh, Pittsburgh, Pennsylvania 15261, United States.

With continually increased computer power, molecular mechanics force field-based approaches, such as the endpoint methods of molecular mechanics Poisson-Boltzmann surface area (MM-PBSA) and molecular mechanics generalized Born surface area (MM-GBSA), have been routinely applied in both drug lead identification and optimization. However, the MM-PB/GBSA method is not as accurate as the pathway-based alchemical free energy methods, such as thermodynamic integration (TI) or free energy perturbation (FEP). Although the pathway-based methods are more rigorous in theory, they suffer from slow convergence and computational cost. Moreover, choosing adequate perturbation routes is also crucial for the pathway-based methods. Recently, we proposed a new method, coined extended linear interaction energy (ELIE) method, to overcome some disadvantages of the MM-PB/GBSA method to improve the accuracy of binding free energy calculation. In this work, we have systematically assessed this approach using in total 229 protein-ligand complexes for eight protein targets. Our results showed that ELIE performed much better than the molecular docking and MM-PBSA method in terms of root-mean-square error (RMSE), correlation coefficient (), predictive index (PI), and Kendall's τ. The mean values of PI, , and τ are 0.62, 0.58, and 0.44 for ELIE calculations. We also explored the impact of the length of simulation, ranging from 1 to 100 ns, on the performance of binding free energy calculation. In general, extending simulation length up to 25 ns could significantly improve the performance of ELIE, while longer molecular dynamics (MD) simulation does not always perform better than short MD simulation. Considering both the computational efficiency and achieved accuracy, ELIE is adequate in filling the gap between the efficient docking methods and computationally demanding alchemical free energy methods. Therefore, ELIE provides a practical solution for the routine ranking of compounds in lead optimization.
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http://dx.doi.org/10.1021/acs.jcim.0c00934DOI Listing
December 2020

Pterostilbene inhibits deoxynivalenol-induced oxidative stress and inflammatory response in bovine mammary epithelial cells.

Toxicon 2021 Jan 9;189:10-18. Epub 2020 Nov 9.

College of Animal Sciences, Jilin University, Changchun, 130062, China. Electronic address:

More and more studies have showed that tricothecene mycotoxin, deoxynivalenol (DON) caused cytotoxicity in mammary alveolar cells-large T antigen cells (MAC-T). Therefore, research on reducing the cytotoxicity of DON has gradually attracted attention. In this study, we aim to explore the potential of pterostilbene (PTE) to protect MAC-T cells from DON-induced oxidative stress and inflammatory response. MAC-T cells were treated with 0.25 μg/mL DON or 2.0504 μg/mL PTE or 0.25 μg/mL DON and 2.0504 μg/mL PTE together, incubated for 9 h. PTE effectively improved cell viability, cell proliferation and total antioxidant capacity (T-AOC), reduced reactive oxygen species (ROS) production and malondialdehyde (MDA), and improved glutathione (GSH) depletion. Moreover, PTE effectively regulated the mRNA levels of nuclear factor erythroid-2-related factor 2 (Nrf2), kelch-like ech-associated protein 1 (Keap1), superoxide dismutase 1 (SOD1) and superoxide dismutase 2 (SOD2). PTE significantly inhibited nuclear factor kappa-B P65 (NF-κB P65), nuclear factor kappa-B P50 (NF-κB P50), cyclooxygenase-2 (COX-2), interleukin-1β (IL-1β), interleukin-6 (IL-6) and monocyte chemotactic protein 1 (MCP-1) mRNA levels in DON-induced MAC-T cells. PTE also significantly reduced inducible nitric oxide synthase (iNOS) and nitric oxide (NO) levels in DON-induced MAC-T cells. Additionally, ELISA revealed that PTE inhibited the expression of tumor necrosis factor-α (TNF-α) and IL-6 proteins produced in DON-induced MAC-T cells. These findings together provided strong evidence to support that PTE can effectively alleviate the damage to cells caused by DON, and it may be used as an effective anti-inflammatory and antioxidant to prevent the damage of mycotoxins to the animal body.
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http://dx.doi.org/10.1016/j.toxicon.2020.11.002DOI Listing
January 2021

Orientation and dynamics of Cu based DNA labels from force field parameterized MD elucidates the relationship between EPR distance constraints and DNA backbone distances.

Phys Chem Chem Phys 2020 Dec;22(46):26707-26719

Department of Chemistry, University of Pittsburgh, PA 15260, USA.

Pulsed electron paramagnetic resonance (EPR) based distance measurements using the recently developed Cu2+-DPA label present a promising strategy for measuring DNA backbone distance constraints. Herein we develop force field parameters for Cu2+-DPA in order to understand the features of this label at an atomic level. We perform molecular dynamics (MD) simulations using the force field parameters of Cu2+-DPA on four different DNA duplexes. The distance between the Cu2+ centers, extracted from the 2 μs MD trajectories, agrees well with the experimental distance for all the duplexes. Further analyses of the trajectory provide insight into the orientation of the Cu2+-DPA inside the duplex that leads to such agreement with experiments. The MD results also illustrate the ability of the Cu2+-DPA to report on the DNA backbone distance constraints. Furthermore, measurement of fluctuations of individual residues showed that the flexibility of Cu2+-DPA in a DNA depends on the position of the label in the duplex, and a 2 μs MD simulation is not sufficient to fully capture the experimental distribution in some cases. Finally, the MD trajectories were utilized to understand the key aspects of the double electron electron resonance (DEER) results. The lack of orientational selectivity effects of the Cu2+-DPA at Q-band frequency is rationalized in terms of fluctuations in the Cu2+ coordination environment and rotameric fluctuations of the label linker. Overall, a combination of EPR and MD simulations based on the Cu2+-DPA labelling strategy can contribute towards understanding changes in DNA backbone conformations during protein-DNA interactions.
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http://dx.doi.org/10.1039/d0cp05016dDOI Listing
December 2020

Efficient formulation of polarizable Gaussian multipole electrostatics for biomolecular simulations.

J Chem Phys 2020 Sep;153(11):114116

Departments of Molecular Biology and Biochemistry, Chemical and Biomolecular Engineering, Materials Science and Engineering, and Biomedical Engineering, Graduate Program in Chemical and Materials Physics, University of California, Irvine, Irvine, California 92697, USA.

Molecular dynamics simulations of biomolecules have been widely adopted in biomedical studies. As classical point-charge models continue to be used in routine biomolecular applications, there have been growing demands on developing polarizable force fields for handling more complicated biomolecular processes. Here, we focus on a recently proposed polarizable Gaussian Multipole (pGM) model for biomolecular simulations. A key benefit of pGM is its screening of all short-range electrostatic interactions in a physically consistent manner, which is critical for stable charge-fitting and is needed to reproduce molecular anisotropy. Another advantage of pGM is that each atom's multipoles are represented by a single Gaussian function or its derivatives, allowing for more efficient electrostatics than other Gaussian-based models. In this study, we present an efficient formulation for the pGM model defined with respect to a local frame formed with a set of covalent basis vectors. The covalent basis vectors are chosen to be along each atom's covalent bonding directions. The new local frame can better accommodate the fact that permanent dipoles are primarily aligned along covalent bonds due to the differences in electronegativity of bonded atoms. It also allows molecular flexibility during molecular simulations and facilitates an efficient formulation of analytical electrostatic forces without explicit torque computation. Subsequent numerical tests show that analytical atomic forces agree excellently with numerical finite-difference forces for the tested system. Finally, the new pGM electrostatics algorithm is interfaced with the particle mesh Ewald (PME) implementation in Amber for molecular simulations under the periodic boundary conditions. To validate the overall pGM/PME electrostatics, we conducted an NVE simulation for a small water box of 512 water molecules. Our results show that to achieve energy conservation in the polarizable model, it is important to ensure enough accuracy on both PME and induction iteration. It is hoped that the reformulated pGM model will facilitate the development of future force fields based on the pGM electrostatics for applications in biomolecular systems and processes where polarization plays crucial roles.
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http://dx.doi.org/10.1063/5.0019560DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7502018PMC
September 2020

A fast and high-quality charge model for the next generation general AMBER force field.

J Chem Phys 2020 Sep;153(11):114502

Department of Pharmaceutical Sciences and Computational Chemical Genomics Screening Center, School of Pharmacy, University of Pittsburgh, Pittsburgh, Pennsylvania 15261, USA.

The General AMBER Force Field (GAFF) has been broadly used by researchers all over the world to perform in silico simulations and modelings on diverse scientific topics, especially in the field of computer-aided drug design whose primary task is to accurately predict the affinity and selectivity of receptor-ligand binding. The atomic partial charges in GAFF and the second generation of GAFF (GAFF2) were originally developed with the quantum mechanics derived restrained electrostatic potential charge, but in practice, users usually adopt an efficient charge method, Austin Model 1-bond charge corrections (AM1-BCC), based on which, without expensive ab initio calculations, the atomic charges could be efficiently and conveniently obtained with the ANTECHAMBER module implemented in the AMBER software package. In this work, we developed a new set of BCC parameters specifically for GAFF2 using 442 neutral organic solutes covering diverse functional groups in aqueous solution. Compared to the original BCC parameter set, the new parameter set significantly reduced the mean unsigned error (MUE) of hydration free energies from 1.03 kcal/mol to 0.37 kcal/mol. More excitingly, this new AM1-BCC model also showed excellent performance in the solvation free energy (SFE) calculation on diverse solutes in various organic solvents across a range of different dielectric constants. In this large-scale test with totally 895 neutral organic solvent-solute systems, the new parameter set led to accurate SFE predictions with the MUE and the root-mean-square-error of 0.51 kcal/mol and 0.65 kcal/mol, respectively. This newly developed charge model, ABCG2, paved a promising path for the next generation GAFF development.
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http://dx.doi.org/10.1063/5.0019056DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7728379PMC
September 2020

Development of Cu-Based Distance Methods and Force Field Parameters for the Determination of PNA Conformations and Dynamics by EPR and MD Simulations.

J Phys Chem B 2020 09 25;124(35):7544-7556. Epub 2020 Aug 25.

Department of Chemistry, University of Pittsburgh, Pittsburgh, Pennsylvania 15260, United States.

Peptide nucleic acids (PNAs) are a promising group of synthetic analogues of DNA and RNA that offer several distinct advantages over the naturally occurring nucleic acids for applications in biosensing, drug delivery, and nanoelectronics. Because of its structural differences from DNA/RNA, methods to analyze and assess the structure, conformations, and dynamics are needed. In this work, we develop synergistic techniques for the study of the PNA conformation. We use CuQ, a Cu complex with 8-hydroxyquinoline (HQ), as an alternative base pair and as a spin label in electron paramagnetic resonance (EPR) distance methods. We use molecular dynamics (MD) simulations with newly developed force field parameters for the spin labels to interpret the distance constraints determined by EPR. We complement these methods by UV-vis and circular dichroism measurements and assess the efficacy of the Cu label on a PNA duplex whose backbone is based on aminoethylglycine and a duplex with a hydroxymethyl backbone modification. We show that the Cu label functions efficiently within the standard PNA and the hydroxymethyl-modified PNA and that the MD parameters may be used to accurately reproduce our EPR findings. Through the combination of EPR and MD, we gain new insights into the PNA structure and conformations as well as into the mechanism of orientational selectivity in Cu EPR at X-band. These results present for the first time a rigid Cu spin label used for EPR distance measurements in PNA and the accompanying MD force fields for the spin label. Our studies also reveal that the spin labels have a low impact on the structure of the PNA duplexes. The combined MD and EPR approach represents an important new tool for the characterization of the PNA duplex structure and provides valuable information to aid in the rational application of PNA at large.
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http://dx.doi.org/10.1021/acs.jpcb.0c05509DOI Listing
September 2020

Molecular mechanism of ultrasound interaction with a blood brain barrier model.

J Chem Phys 2020 Jul;153(4):045104

CNRS, Universite de Paris, UPR9080, Laboratoire de Biochimie Théorique, Paris, France.

The brain is strictly protected by the blood brain barrier preventing the crossing of therapeutics to treat brain diseases. The high and low intensity focused ultrasound methods have been used to temporarily open the blood brain barrier, facilitating the transport of drugs. The methods are very promising because the opening is transient, localized, and noninvasive. However, the molecular mechanism of the opening is unknown, and this limits the development and application of these methods. With this in mind, we carry out a molecular dynamics simulation study to understand the interaction of ultrasound with the cell membrane and the tight junction. Our minimal blood brain barrier model is composed of two lipid bilayers, mimicking two portions of neighboring cells, connected together by a tight junction formed by a pair of two cis-dimers of the claudin-5 protein. Using an experimental ultrasound frequency of 50 MHz, simulations show that at low intensities, ultrasound does not impact the structure of the cell membranes and tight junction, implying that the direct interaction of ultrasound with the blood brain barrier is not responsible for the experimentally observed opening. At high intensities, the ultrasound pulls the monolayers of individual cell membrane lipid bilayers apart, creating air compartments inside the bilayers. This reduces the free energy barrier for the translocation of drugs across the lipid bilayer and enhances drug permeability. At very high intensities, the two monolayers are largely separated, resulting in cell damage and implying that the blood brain barrier is primarily opened at the experimentally observed damaged areas.
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http://dx.doi.org/10.1063/5.0010667DOI Listing
July 2020

Efficacy assessment of ticagrelor versus clopidogrel in Chinese patients with acute coronary syndrome undergoing percutaneous coronary intervention by data mining and machine-learning decision tree approaches.

J Clin Pharm Ther 2020 Oct 6;45(5):1076-1086. Epub 2020 Jul 6.

Department of Clinical Pharmacy, Zhongshan Hospital, Fudan University, Shanghai, China.

What Is Known And Objective: Although ticagrelor has been well-known to improve clinical outcomes in patients undergoing percutaneous coronary intervention (PCI), and its effectiveness and safety have not been well evaluated in Chinese patients. This study aimed to evaluate the effectiveness and safety of ticagrelor in Chinese patients. In order to find potential effect modifiers on the drug effects, a decision tree method was performed to detect interactions between treatment and patient characteristics in an automatic and systematic manner.

Methods: This retrospective study included acute coronary syndrome (ACS) patients who underwent PCI and received either ticagrelor (N = 250) or clopidogrel (N = 291) while hospitalized between August 2014 and August 2015. After propensity score matching, Kaplan-Meier analysis was used to study the event-free survival against major adverse cardiovascular events (MACE, primary efficacy outcome, defined as the composite of cardiac death, non-fatal myocardial infarction [MI], stroke, restenosis and target vessel revascularization [TVR]), re-hospitalization, the need for urgent re-PCI (secondary efficacy outcome) and bleeding events (safety outcome) within 12 months of the PCI date. To search for effect modifiers of the two antiplatelet therapies, a machine-learning decision tree algorithm was conducted to predict re-hospitalization status.

Results: After propensity score matching (N = 442), ticagrelor and clopidogrel had no significant difference in MACE, re-hospitalization and bleeding. The decision tree analysis showed that the number of diseased vessels modulated the effect of ticagrelor and clopidogrel on re-hospitalization rates. In single-vessel disease (SVD) patients, ticagrelor was associated with lower hazards than clopidogrel for all efficacy outcomes: MACE (HR = 0.190, 95% CI: 0.042-0.866), re-hospitalization (HR = 0.296, 95% CI: 0.108-0.808), urgent re-PCI (HR = 0.249, 95% CI: 0.069-0.895), bleeding (HR = 1.006, 95% CI: 0.063-16.129). However, in multi-vessel disease (MVD) patients, the two treatments did not show significant difference.

What Is New And Conclusion: In the general patient population, there was no significant difference between ticagrelor and clopidogrel on the hazard of MACE. However, ticagrelor achieved a better effectiveness than clopidogrel in patients with SVD. This pilot study provides scientific basis to call for a large-scale prospective study in this population.
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http://dx.doi.org/10.1111/jcpt.13172DOI Listing
October 2020

Infrared Laser-Induced Amyloid Fibril Dissociation: A Joint Experimental/Theoretical Study on the GNNQQNY Peptide.

J Phys Chem B 2020 07 8;124(29):6266-6277. Epub 2020 Jul 8.

Laboratoire de Biochimie Théorique, CNRS, Université de Paris, UPR9080, Paris, France.

Neurodegenerative diseases are usually characterized by plaques made of well-ordered aggregates of distinct amyloid proteins. Dissociating these very stable amyloid plaques is a critical clinical issue. In this study, we present a joint mid-infrared free electron laser experiment/nonequilibrium molecular dynamics simulation to understand the dissociation process of a representative example GNNQQNY fibril. By tuning the laser frequency to the amide I band of the fibril, the resonance takes place and dissociation is occurred. With the calculated and observed wide-angle X-ray scattering profiles and secondary structures before and after laser irradiation being identical, we can propose a dissociation mechanism with high confidence from our simulations. We find that dissociation starts in the core of the fibrils by fragmenting the intermolecular hydrogen bonds and separating the peptides and then propagates to the fibril extremities leading to the formation of unstructured expanded oligomers. We suggest that this should be a generic mechanism of the laser-induced dissociation of amyloid fibrils.
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http://dx.doi.org/10.1021/acs.jpcb.0c05385DOI Listing
July 2020

Landscape of drug-resistance mutations in kinase regulatory hotspots.

Brief Bioinform 2021 May;22(3)

More than 48 kinase inhibitors (KIs) have been approved by Food and Drug Administration. However, drug-resistance (DR) eventually occurs, and secondary mutations have been found in the previously targeted primary-mutated cancer cells. Cancer and drug research communities recognize the importance of the kinase domain (KD) mutations for kinasopathies. So far, a systematic investigation of kinase mutations on DR hotspots has not been done yet. In this study, we systematically investigated four types of representative mutation hotspots (gatekeeper, G-loop, αC-helix and A-loop) associated with DR in 538 human protein kinases using large-scale cancer data sets (TCGA, ICGC, COSMIC and GDSC). Our results revealed 358 kinases harboring 3318 mutations that covered 702 drug resistance hotspot residues. Among them, 197 kinases had multiple genetic variants on each residue. We further computationally assessed and validated the epidermal growth factor receptor mutations on protein structure and drug-binding efficacy. This is the first study to provide a landscape view of DR-associated mutation hotspots in kinase's secondary structures, and its knowledge will help the development of effective next-generation KIs for better precision medicine.
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http://dx.doi.org/10.1093/bib/bbaa108DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8138826PMC
May 2021

Fast Identification of Possible Drug Treatment of Coronavirus Disease -19 (COVID-19) Through Computational Drug Repurposing Study.

Authors:
Junmei Wang

ChemRxiv 2020 Feb 21. Epub 2020 Feb 21.

The recent outbreak of novel coronavirus disease -19 (COVID-19) calls for and welcomes possible treatment strategies using drugs on the market. It is very efficient to apply computer-aided drug design techniques to quickly identify promising drug repurposing candidates, especially after the detailed 3D-structures of key virous proteins are resolved. Taking the advantage of a recently released crystal structure of COVID-19 protease in complex with a covalently-bonded inhibitor, N3,1 I conducted virtual docking screening of approved drugs and drug candidates in clinical trials. For the top docking hits, I then performed molecular dynamics simulations followed by binding free energy calculations using an endpoint method called MM-PBSA-WSAS.2-4 Several promising known drugs stand out as potential inhibitors of COVID-19 protease, including Carfilzomib, Eravacycline, Valrubicin, Lopinavir and Elbasvir. Carfilzomib, an approved anti-cancer drug acting as a proteasome inhibitor, has the best MM-PBSA-WSAS binding free energy, -13.82 kcal/mol. Streptomycin, an antibiotic and a charged molecule, also demonstrates some inhibitory effect, even though the predicted binding free energy of the charged form (-3.82 kcal/mol) is not nearly as low as that of the neutral form (-7.92 kcal/mol). One bioactive, PubChem 23727975, has a binding free energy of -12.86 kcal/mol. Detailed receptor-ligand interactions were analyzed and hot spots for the receptor-ligand binding were identified. I found that one hotspot residue HIS41, is a conserved residue across many viruses including COVID-19, SARS, MERS, and HCV. The findings of this study can facilitate rational drug design targeting the COVID-19 protease.
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http://dx.doi.org/10.26434/chemrxiv.11875446DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7263765PMC
February 2020

Accurate Preoperative Distinction of Intracranial Hemangiopericytoma From Meningioma Using a Multihabitat and Multisequence-Based Radiomics Diagnostic Technique.

Front Oncol 2020 19;10:534. Epub 2020 May 19.

Department of Neurosurgery, Beijing Tiantan Hospital, Capital Medical University, Beijing, China.

Intracranial hemangiopericytoma (IHPC) and meningioma are both meningeal neoplasms, but they have extremely different malignancy and outcomes. Because of their similar radiological characteristics, they are difficult to distinguish prior to surgery, leading to a high rate of misdiagnosis. We enrolled 292 patients (IHPC, 155; meningiomas, 137) with complete clinic-radiological and histopathological data, from a 10-year database established at Tiantan hospital. Radiomics analysis of tumor and peritumoral edema was performed on multisequence magnetic resonance images, and a fusion radiomics signature was generated using a machine-learning strategy. By combining clinic-radiological data with the fusion radiomics signature, we developed an integrated diagnostic approach that we named the IHPC and Meningioma Diagnostic Tool (HMDT). The HMDT displayed remarkable diagnostic ability, with areas under the curve (AUCs) of 0.985 and 0.917 in the training and validation cohorts, respectively. The calibration curve showed excellent agreement between the diagnosis predicted by HMDT and the histological outcome, with -values of 0.801 and 0.622 for the training and the validation cohorts, respectively. Cross-validation showed no statistical difference across three divisions of the cohort, with average AUCs of 0.980 and 0.941 for the training and validation cohorts, respectively. Stratification analysis showed consistent performance of the HMDT in distinguishing IHPC from highly misdiagnosed subgroups of grade I meningioma and angiomatous meningioma (AM) with AUCs of 0.913 and 0.914 in the validation cohorts for the two subgroups. By integrating clinic-radiological information with radiomics signature, the proposed HMDT could assist in preoperative diagnosis to distinguish IHPC from meningioma, providing the basis for strategic decisions regarding surgery.
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http://dx.doi.org/10.3389/fonc.2020.00534DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7248296PMC
May 2020

Somatic SF3B1 hotspot mutation in prolactinomas.

Nat Commun 2020 05 19;11(1):2506. Epub 2020 May 19.

Department of Cell Biology, Beijing Neurosurgical Institute, Capital Medical University, Beijing, 100070, China.

The genetic basis and corresponding clinical relevance of prolactinomas remain poorly understood. Here, we perform whole genome sequencing (WGS) on 21 patients with prolactinomas to detect somatic mutations and then validate the mutations with digital polymerase chain reaction (PCR) analysis of tissue samples from 227 prolactinomas. We identify the same hotspot somatic mutation in splicing factor 3 subunit B1 (SF3B1) in 19.8% of prolactinomas. These patients with mutant prolactinomas display higher prolactin (PRL) levels (p = 0.02) and shorter progression-free survival (PFS) (p = 0.02) compared to patients without the mutation. Moreover, we identify that the SF3B1 mutation causes aberrant splicing of estrogen related receptor gamma (ESRRG), which results in stronger binding of pituitary-specific positive transcription factor 1 (Pit-1), leading to excessive PRL secretion. Thus our study validates an important mutation and elucidates a potential mechanism underlying the pathogenesis of prolactinomas that may lead to the development of targeted therapeutics.
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http://dx.doi.org/10.1038/s41467-020-16052-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7237453PMC
May 2020