Publications by authors named "Weiwei Han"

89 Publications

Molecular Dockings and Molecular Dynamics Simulations Reveal the Potency of Different Inhibitors against Xanthine Oxidase.

ACS Omega 2021 May 22;6(17):11639-11649. Epub 2021 Apr 22.

Key Laboratory for Molecular Enzymology and Engineering of Ministry of Education, School of Life Science, Jilin University, 2699 Qianjin Street, Changchun 130012, China.

Xanthine oxidase (XO), which can catalyze the formation of xanthine or hypoxanthine to uric acid, is the most important target of gout. To explore the conformational changes for inhibitor binding, molecular dockings and molecular dynamics simulations were performed. Docking results indicated that three inhibitors had similar pose binding to XO. Molecular dynamics simulations showed that the binding of three inhibitors influenced the secondary structure changes in XO. After binding to the inhibitor, the peptide Phe798-Leu814 formed different degrees of unhelix, while for the peptide Glu1065-Ser1075, only a partial helix region was formed when allopurinol was bound. Through the protein structure analysis in the simulation process, we found that the distance between the active residues Arg880 and Thr1010 was reduced and the distance between Glu802 and Thr1010 was increased after the addition of inhibitors. The above simulation results showed the similarities and differences of the interaction between the three inhibitors binding to the protein. MM-PBSA calculations suggested that, among three inhibitors, allopurinol had the best binding effect with XO followed by daidzin and puerarin. This finding was consistent with previous experimental data. Our results can provide some useful clues for further gout treatment research.
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http://dx.doi.org/10.1021/acsomega.1c00968DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8154014PMC
May 2021

The Protection of Crocin Against Ulcerative Colitis and Colorectal Cancer via Suppression of NF-κB-Mediated Inflammation.

Front Pharmacol 2021 18;12:639458. Epub 2021 Mar 18.

School of Life Sciences, Jilin University, Changchun, China.

In China, the incidence of ulcerative colitis (UC) is increasing every year, but the etiology of UC remains unclear. UC is known to increase the risk of colorectal cancer (CRC). The aim of this study was to investigate the protective effects of crocin against UC and CRC in mouse models. Crocin was used to treat the dextran sodium sulfate (DSS)-induced UC mice for 3 weeks, and Apc/Gpt mice with colorectal cancer for 8 weeks. Proteomics screening was used to detect changes in the protein profiles of colon tissues of UC mice. Enzyme-linked immunosorbent assays and western blot were used to verify these changes. Crocin strongly reduced the disease activity index scores of UC mice, and improved the pathological symptoms of the colonic epithelium. The anti-inflammatory effects of crocin were indicated by its regulation of the activity of various cytokines, such as interleukins, via the modulation of nuclear factor kappa-B (NF-κB) signaling. Crocin significantly suppressed tumor growth in Apc/Gpt mice and ameliorated pathological alterations in the colon and liver, but had no effects on spleen and kidney. Additionally, crocin significantly decreased the concentrations of interleukins and tumor necrosis factor-α in the sera and colon tissues, suggesting its anti-inflammatory effects related to NF-κB signaling. Finally, 12-h incubation of SW480 cells with crocin caused cell cycle arrest, enhanced the apoptotic rate, promoted the dissipation of mitochondrial membrane potential, and the over-accumulation of reactive oxygen species. From the theoretical analyses, phosphorylated residues on S536 may enhance the protein-protein interactions which may influence the conformational changes in the secondary structure of NF-κB. The protective effects of crocin on UC and CRC were due to its suppression of NF-κB-mediated inflammation.
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http://dx.doi.org/10.3389/fphar.2021.639458DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8025585PMC
March 2021

Conformational Changes of Glutamine 5'-Phosphoribosylpyrophosphate Amidotransferase for Two Substrates Analogue Binding: Insight from Conventional Molecular Dynamics and Accelerated Molecular Dynamics Simulations.

Front Chem 2021 26;9:640994. Epub 2021 Feb 26.

Key Laboratory for Molecular Enzymology and Engineering of Ministry of Education, Engineering Laboratory for AIDS Vaccine, School of Life Science, Jilin University, Changchun, China.

Glutamine 5'-phosphoribosylpyrophosphate amidotransferase (GPATase) catalyzes the synthesis of phosphoribosylamine, pyrophosphate, and glutamate from phosphoribosylpyrophosphate, as well as glutamine at two sites (i.e., glutaminase and phosphoribosylpyrophosphate sites), through a 20 Å NH channel. In this study, conventional molecular dynamics (cMD) simulations and enhanced sampling accelerated molecular dynamics (aMD) simulations were integrated to characterize the mechanism for coordination catalysis at two separate active sites in the enzyme. Results of cMD simulations illustrated the mechanism by which two substrate analogues, namely, DON and cPRPP, affect the structural stability of GPATase from the perspective of dynamic behavior. aMD simulations obtained several key findings. First, a comparison of protein conformational changes in the complexes of GPATase-DON and GPATase-DON-cPRPP showed that binding cPRPP to the PRTase flexible loop (K326 to L350) substantially effected the formation of the R73-DON salt bridge. Moreover, only the PRTase flexible loop in the GPATase-DON-cPRPP complex could remain closed and had sufficient space for cPRPP binding, indicating that binding of DON to the glutamine loop had an impact on the PRTase flexible loop. Finally, both DON and cPRPP tightly bonded to the two domains, thereby inducing the glutamine loop and the PRTase flexible loop to move close to each other. This movement facilitated the transfer of NH3 via the NH3 channel. These theoretical results are useful to the ongoing research on efficient inhibitors related to GPATase.
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http://dx.doi.org/10.3389/fchem.2021.640994DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7953260PMC
February 2021

A potential method to determine pigment particle size on ancient murals using laser induced breakdown spectroscopy and chemometric analysis.

Anal Methods 2021 03 2;13(11):1381-1391. Epub 2021 Mar 2.

Key Laboratory of Atomic and Molecular Physics & Functional Materials of Gansu Province, College of Physics and Electronic Engineering, Northwest Normal University, Lanzhou, 730070, China.

Information on pigment sizes in mural samples is a key factor in determining the suitable processes of possible restoration and conservation on ancient murals and is also significant for the investigation of a mural's historic value and analysis of its technical process. Thus, in this paper, the green painted layers composed of different pigment sizes were analyzed by laser-induced breakdown spectroscopy. First, a parametric study was undertaken to optimize the LIBS signal to noise ratio and decrease fluctuations. Then, the variation of LIBS signal with pigment size was studied on simulated mural samples. Finally, a classifiable model of pigment sizes was built by coupling with the PCA method and was successfully applied to classify pigment sizes on real mural pieces.
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http://dx.doi.org/10.1039/d0ay01546fDOI Listing
March 2021

Extraction, Radical Scavenging Activities, and Chemical Composition Identification of Flavonoids from Sunflower ( L.) Receptacles.

Molecules 2021 Jan 14;26(2). Epub 2021 Jan 14.

School of Life Sciences, Jilin University, Changchun 130012, China.

This study was focused on extraction, radical scavenging activities, and chemical composition identification of total flavonoids in sunflower ( L.) receptacles (TFSR). We investigated the optimal extract parameters of TFSR using response surface methodology. The highest yield of TFSR was 1.04% with the ethanol concentration 58%, the material-to-liquid ratio 1:20 (/), the extraction time 2.6 h, and the extraction temperature 67 °C. The results of radical scavenging activities showed that ethyl acetate fraction (EAF) was the strongest by using 2-diphenyl-1-picrylhydrazyl (DPPH), 2, 2'-azino-bis (3-ethylbenzo thiazoline-6-sulfonic acid) (ABTS) and iron ion reducing analysis. The EAF had the highest flavonoids contents. Four fractions A, B, C and D were enrichment from EAF by polyamide resin. Fraction B had the highest flavonoids content. Thirteen chemical components of flavonoids in fraction B were first identified by Ultimate 3000 Nano LC System coupled to a Q Exactive HF benchtop Orbitrap mass spectrometer (UHPLC-HRMS/MS). Among of the thirteen chemical components, isoquercetin and daidzein were identified accurately by comparing with standard samples. Radical scavenging analysis showed that isoquercetin and EAF had strong activities. Therefore, sunflower receptacles can be used as a source of natural flavonoids. TFSR as a natural radical scavenger has potential applications in pharmaceutical industry.
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http://dx.doi.org/10.3390/molecules26020403DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7828773PMC
January 2021

Low DAPK1 expression correlates with poor prognosis and sunitinib resistance in clear cell renal cell carcinoma.

Aging (Albany NY) 2020 11 16;13(2):1842-1858. Epub 2020 Nov 16.

Department of Urology, The Central Hospital of Wuhan, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.

We investigated the prognostic significance of Death-Associated Protein Kinase 1 (DAPK1) and its role in sunitinib resistance in clear cell renal cell carcinoma (ccRCC). DAPK1 mRNA levels were significantly lower in tumor tissues than normal kidney tissues in TCGA-KIRC dataset (n=428). Both overall survival and disease-free survival were significantly shorter in ccRCC patients with low DAPK1 expression than those with high DAPK1 expression. Receiver operating characteristic curve analysis showed that low DAPK1 expression correlated with poor prognosis in ccRCC patients. Multivariate analysis confirmed that DAPK1 expression was an independent prognostic indicator in ccRCC. Gene set enrichment analysis showed that low DAPK1 expression correlates with upregulation of pathways related to metastasis, drug resistance, hypoxia and invasiveness in ccRCC patients. Sunitinib-resistant ccRCC cells show significantly lower DAPK1 mRNA and protein levels than sunitinib-sensitive ccRCC cells. DAPK1 overexpression enhances apoptosis in sunitinib-resistant ccRCC cells via the ATF6-dependent ER stress pathway. Xenograft tumors derived from DAPK1-overxpressing ccRCC cells were significantly smaller than the controls in nude mice. Our finding demonstrates that low DAPK1 expression is an independent prognostic indicator that correlates with ccRCC progression and sunitinib resistance.
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http://dx.doi.org/10.18632/aging.103638DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7880360PMC
November 2020

[A case report of congenital sensorineural deafness caused by novel mutation in Usher1C and related literature analysis].

Lin Chung Er Bi Yan Hou Tou Jing Wai Ke Za Zhi 2020 Jun;34(6):562-564

To study the clinical features and causes of congenital Usher hearing loss in one child. Clinical examination, audiological tests, visual acuity examination were conducted in the proband and its family members, and second-generation sequencing technology for deafness gene detection was employed. The proband exhibited profound sensorineural deafness(hearing threshold>90 dB nHL). There was no visual loss after follow-up. Other family members had no history of hearing loss. The gene test indicated that the proband had a frameshift mutation for the thymine(T) deletion at the 1527 site of the Usher1C gene. The mutation was a homozygous mutation, and was from the father and the mother, respectively, which caused the truncation of the encoded protein. Normal function, Usher syndrome or non-syndromic deafness DFNB18 can occur. This is the first case in China demonstrating congenital deafness due to homozygous mutation of Usher1C gene c. 1527delT. This study enriches the gene spectrum of deafness in China.
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http://dx.doi.org/10.13201/j.issn.2096-7993.2020.06.019DOI Listing
June 2020

Leveraging Systematic Functional Analysis to Benchmark an Framework Distinguishes Driver from Passenger MEK Mutants in Cancer.

Cancer Res 2020 10 8;80(19):4233-4243. Epub 2020 Jul 8.

Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York.

Despite significant advances in cancer precision medicine, a significant hurdle to its broader adoption remains the multitude of variants of unknown significance identified by clinical tumor sequencing and the lack of biologically validated methods to distinguish between functional and benign variants. Here we used functional data on and mutations generated in real-time within a co-clinical trial framework to benchmark the predictive value of a three-part methodology. Our computational approach to variant classification incorporated hotspot analysis, three-dimensional molecular dynamics simulation, and sequence paralogy. prediction accurately distinguished functional from benign and mutants, yet drug sensitivity varied widely among activating mutant alleles. These results suggest that multifaceted modeling can inform patient accrual to MEK/ERK inhibitor clinical trials, but computational methods need to be paired with laboratory- and clinic-based efforts designed to unravel variabilities in drug response. SIGNIFICANCE: Leveraging prospective functional characterization of MEK1/2 mutants, it was found that hotspot analysis, molecular dynamics simulation, and sequence paralogy are complementary tools that can robustly prioritize variants for biologic, therapeutic, and clinical validation..
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http://dx.doi.org/10.1158/0008-5472.CAN-20-0865DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7541597PMC
October 2020

Increased Otolin-1 in Serum as a Potential Biomarker for Idiopathic Benign Paroxysmal Positional Vertigo Episodes.

Front Neurol 2020 13;11:367. Epub 2020 May 13.

Department of Neurology, Hwa Mei Hospital, University of Chinese Academy of Science, Ningbo, China.

Otolin-1, a main specific otoconia matrix protein, passes through the labyrinth-blood barrier and is detectable in peripheral blood. Serum otolin-1 levels differ between patients with benign paroxysmal positional vertigo (BPPV) and healthy controls and are significantly age-related, increasing in healthy controls with age, suggesting that serum otolin-1 levels reflect otolith status. The aim of this study was to determine whether otolin-1 levels change during vertigo episodes in patients with BPPV and whether any change is specific and sensitive enough for BPPV episodes. Patients diagnosed with idiopathic BPPV during an acute episode were included in the study from May 2017 to May 2018. Blood samples were drawn before patients were treated with canalith-repositioning maneuvers. Serum otolin-1 levels were compared between 78 patients and 121 age- and sex-matched healthy individuals. There were no significant differences between the groups in the age distribution, sex ratio, body mass index, clinical history, routine blood parameters, or total protein, albumin, uric acid, creatinine, blood urea nitrogen and lipid profiles ( > 0.05). Serum levels of otolin-1 were significantly higher in BPPV patients than in healthy controls ( < 0.001). Receiver operating characteristic analysis revealed that a serum otolin-1 value of 299.45 pg/ml was the optimal cut-off value to discriminate patients with BPPV from healthy controls (area under the curve 0.757, 95% CI 0.687~0.826) with a sensitivity of 67.9% and a specificity of 72.7%. Serum levels of otolin-1 may be a potential biomarker for BPPV episodes.
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http://dx.doi.org/10.3389/fneur.2020.00367DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7237635PMC
May 2020

A Novel Mutation in a Chinese Family with Waardenburg Syndrome Type 1.

Genet Test Mol Biomarkers 2020 May 3;24(5):249-255. Epub 2020 Apr 3.

Department of Otolaryngology, 1st Affiliated Hospital of Kunming Medical University, Kunning, China.

To determine the clinical characteristics and genetic cause of Waardenburg syndrome type 1 (WS1) in a Chinese family. Evaluations, including history, clinical features, and audiological tests, were performed on the proband and her parents. Genetic analyses were performed targeting 144 known deafness genes using a next-generation sequencing panel. Bioinformatic analyses were used to analyze the candidate mutation. The proband and her parents suffered from congenital bilateral profound hearing loss. Her mother exhibited bilateral blue irides. WS1 was diagnosed in the proband and her mother according to the Waardenburg syndrome consortium criteria: the calculated W index of the proband was 2.39 and that of her mother was 2.31. A novel mutation c.1076_1077del (p.Thr359fs) in exon 7 of the gene was identified in the proband and her mother that was absent in the father and controls. Mutations in exon 7 of the gene are rare. We identified a novel frameshift mutation in exon 7 of the gene that we determined was responsible for WS1 in this family.
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http://dx.doi.org/10.1089/gtmb.2019.0231DOI Listing
May 2020

Computational Study on the Effect of Inactivating/Activating Mutations on the Inhibition of MEK1 by Trametinib.

Int J Mol Sci 2020 Mar 21;21(6). Epub 2020 Mar 21.

Key Laboratory for Molecular Enzymology and Engineering of Ministry of Education, School of Life Science, Jilin University, 2699 Qianjin Street, Changchun 130012, China.

Activation of the mitogen-activated protein kinase (MAPK) signaling pathway regulated by human MAP kinase 1 (MEK1) is associated with the carcinogenesis and progression of numerous cancers. In addition, two active mutations (P124S and E203K) have been reported to enhance the activity of MEK1, thereby eventually leading to the tumorigenesis of cancer. Trametinib is an MEK1 inhibitor for treating EML4-ALK-positive, EGFR-activated, and KRAS-mutant lung cancers. Therefore, in this study, molecular docking and molecular dynamic (MD) simulations were performed to explore the effects of inactive/active mutations (A52V/P124S and E203K) on the conformational changes of MEK1 and the changes in the interaction of MEK1 with trametinib. Moreover, steered molecular dynamic (SMD) simulations were further utilized to compare the dissociation processes of trametinib from the wild-type (WT) MEK1 and two active mutants (P124S and E203K). As a result, trametinib had stronger interactions with the non-active MEK1 (WT and A52V mutant) than the two active mutants (P124S and E203K). Moreover, two active mutants may make the allosteric channel of MEK1 wider and shorter than that of the non-active types (WT and A52V mutant). Hence, trametinib could dissociate from the active mutants (P124S and E203K) more easily compared with the WT MEK1. In summary, our theoretical results demonstrated that the active mutations may attenuate the inhibitory effects of MEK inhibitor (trametinib) on MEK1, which could be crucial clues for future anti-cancer treatment.
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http://dx.doi.org/10.3390/ijms21062167DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7139317PMC
March 2020

Molecular mechanisms of metal ions in regulating the catalytic efficiency of D-psicose 3-epimerase revealed by multiple short molecular dynamic simulations and free energy predictions.

J Biomol Struct Dyn 2021 Mar 23;39(5):1887-1897. Epub 2020 Mar 23.

Key Laboratory for Molecular Enzymology and Engineering of Ministry of Education, School of Life Science, Jilin University, Changchun, China.

Communicated by Ramaswamy H. Sarma.
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http://dx.doi.org/10.1080/07391102.2020.1737232DOI Listing
March 2021

The Effect of the Hydrate Antiagglomerant on Hydrate Crystallization at the Oil-Water Interface.

ACS Omega 2020 Feb 13;5(7):3315-3321. Epub 2020 Feb 13.

College of Chemistry and Chemical Engineering, Xi'an Shiyou University, Xi'an 710065, China.

Clathrate hydrates are ice-like compounds consisting of small gas molecules enclosed in water molecule cages. The formation of gas hydrate in oil and gas pipelines may result in flow assurance failure and serious safety and environmental concerns. Antiagglomeration is a promising method to mitigate gas hydrate risks in hydrocarbon flowlines. Morphological behavior of hydrates in the presence of antiagglomerants can provide important information on the antiagglomeration mechanisms. This study reports the visual observations of the morphology of hydrate formed with a water droplet immersed in cyclopentane with and without the presence of a hydrate antiagglomerant (AA). The effect of AA on the hydrate crystal growth was investigated. The AA exhibited a kinetic inhibition effect. With no AA, a faceted hydrate shell formed around the water droplet was observed. The subcooling can affect the rate of lateral growth. Higher subcooling facilitates hydrate growth. With the presence of 0.04 wt % AA, a hairy and porous morphology of hydrate was observed. At higher AA concentrations, a vertical type of growth after the lateral growth of the hydrate shell was observed. This is probably the first report of vertical growth of cyclopentane hydrate formed with a water droplet. A hypothesis is proposed to explain the vertical growth mechanism of the hydrate crystals.
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http://dx.doi.org/10.1021/acsomega.9b03395DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7045306PMC
February 2020

How Different Substitution Positions of F, Cl Atoms in Benzene Ring of 5-Methylpyrimidine Pyridine Derivatives Affect the Inhibition Ability of EGFR Inhibitors: A Molecular Dynamics Simulation Study.

Molecules 2020 Feb 18;25(4). Epub 2020 Feb 18.

Laboratory of Theoretical and Computational Chemistry, Institute of Theoretical Chemistry, Jilin University, Changchun 130023, China.

Lung cancer is the most frequent cause of cancer-related deaths worldwide, and mutations in the kinase domain of the epidermal growth factor receptor (EGFR) are a common cause of non-small-cell lung cancers, which is a major subtype of lung cancers. Recently, a series of 5-methylpyrimidine-pyridinone derivatives have been designed and synthesized as novel selective inhibitors of EGFR and EGFR mutants. However, the binding-based inhibition mechanism has not yet been determined. In this study, we carried out molecular dynamic simulations and free-energy calculations for EGFR derivatives to fill this gap. Based on the investigation, the three factors that influence the inhibitory effect of inhibitors are as follows: (1) The substitution site of the Cl atom is the main factor influencing the activity through steric effect; (2) The secondary factors are repulsion between the F atom (present in the inhibitor) and Glu762, and the blocking effect of Lys745 on the phenyl ring of the inhibitor. (3) The two factors function synergistically to influence the inhibitory capacity of the inhibitor. The theoretical results of this study can provide further insights that will aid the design of oncogenic EGFR inhibitors with high selectivity.
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http://dx.doi.org/10.3390/molecules25040895DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7071101PMC
February 2020

Decorated nickel phosphide nanoparticles with nitrogen and phosphorus co-doped porous carbon for enhanced electrochemical water splitting.

J Colloid Interface Sci 2020 May 11;567:393-401. Epub 2020 Feb 11.

School of Chemical Engineering and Technology, Tianjin University, Tianjin 300050, China. Electronic address:

A novel free-standing electrode consisting of nickel phosphide (NiP) nanoparticles on nitrogen and phosphorus co-doped porous carbon (NPC) are synthesized on carbon cloth (CC). Polyaniline (PANI) and nickel (Ni) are sequentially electro-deposited on the surface of CC, which are then transformed into NPC and NiP by an in-situ carbonization-phosphorization combined process. The electrode surface is distributed with large amounts of uniform macropores, which could expose more active sites and enhance the interfacial exchange with the electrolyte. The [email protected]@CC electrode delivers early overpotentials of 92 and 280 mV vs. Reversible Hydrogen Electrode (RHE) at 10 mA cm for hydrogen evolution reaction (HER) and oxygen evolution reaction (OER) in alkaline condition, respectively. The electrolytic cell with [email protected]@CC electrode both as anode and cathode can achieve 10 mA cm at a small bias of 1.54 V for the overall water splitting. Density functional theory (DFT) calculation indicates that combination with NiP and NPC can decrease Gibbs free energy for H* adsorption (ΔG) and increase charge density on the interface, thus could lead to the enhanced activity for water splitting. The free-standing and noble-metal free [email protected]@CC electrode is stable, highly active and cost effective, thus have great potential for the hydrogen production.
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http://dx.doi.org/10.1016/j.jcis.2020.02.033DOI Listing
May 2020

CFIm25-regulated lncRNA acv3UTR promotes gastric tumorigenesis via miR-590-5p/YAP1 axis.

Oncogene 2020 04 17;39(15):3075-3088. Epub 2020 Feb 17.

Department of Gastrointestinal Surgery, Shandong Cancer Hospital and Institute, Jinan, China.

Accumulating evidences indicate that 3'UTR of the coding gene can act as crucial regulators in gastric cancer (GC). However, the detailed mechanisms and responsive targets are not well established. Here, we found that acvr1b gene 3'UTR (acv3UTR) was elevated in GC tissue, the expression of which was significantly correlated with advanced pTNM-stage and poor outcome in clinical patients. Forced expression of acv3UTR promoted GC cells growth in vitro and in vivo. Mechanistically, our results suggested that acv3UTR functioned as an oncogenic competing endogenous RNA via sponging miR-590-5p and enhancing YAP1 level. Tumor suppressor miR-590-5p was a molecular module in acv3UTR regulatory axis, the forced expression of which led to impairing of oncogenic potential of acv3UTR. The positive correlation of acv3UTR and YAP1 expression, and the negative correlation of acv3UTR and miR-590-5p expression, were verified in GC patients. Moreover, CFIm25 was identified as a key regulator contributing to acv3UTR aberrant expression in GC binding to UGUA-264 motif. Overall, our finding defines a mechanism for understanding the potential role of acv3UTR transcription in GC tumorigenesis, and indicates a correlation between 3'UTR trans-regulatory effect and GC development.
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http://dx.doi.org/10.1038/s41388-020-1213-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7142022PMC
April 2020

A Master Regulator of Bacteroides thetaiotaomicron Gut Colonization Controls Carbohydrate Utilization and an Alternative Protein Synthesis Factor.

mBio 2020 01 28;11(1). Epub 2020 Jan 28.

Department of Microbial Pathogenesis, Yale School of Medicine, New Haven, Connecticut, USA

Microbial colonization of the mammalian gut is largely ascribed to the ability to utilize nutrients available in that environment. To understand how beneficial microbes establish a relationship with their hosts, it is crucial to determine what other abilities promote gut colonization. We now report that colonization of the murine gut by the beneficial microbe requires activation of a putative translation factor by the major transcriptional regulator of gut colonization and carbohydrate utilization. To ascertain how this regulator-called BT4338-promotes gut colonization, we identified BT4338-regulated genes and BT4338-bound DNA sequences. Unexpectedly, the gene whose expression was most reduced upon inactivation was , specifying a putative translation factor. We determined that activation by BT4338 is conserved in another species and essential for gut colonization in because a mutant lacking the BT4338 binding site in the promoter exhibited a colonization defect similar to that of a mutant lacking the gene. Furthermore, we demonstrated that BT4338 promotes gut colonization independently of its role in carbohydrate utilization because the gene was dispensable for utilization of carbohydrates that depend on Our findings suggest that microbial gut colonization requires the use of alternative protein synthesis factors. The bacteria occupying the mammalian gut have evolved unique strategies to thrive in their environment. organisms, which often comprise 25 to 50% of the human gut microbiota, derive nutrients from structurally diverse complex polysaccharides, commonly called dietary fibers. This ability requires an expansive genetic repertoire that is coordinately regulated to achieve expression of those genes dedicated to utilizing only those dietary fibers present in the environment. Here we identify the global regulon of a transcriptional regulator necessary for dietary fiber utilization and gut colonization. We demonstrate that this transcription factor regulates hundreds of genes putatively involved in dietary fiber utilization as well as a putative translation factor dispensable for growth on such nutrients but necessary for survival in the gut. These findings suggest that gut bacteria coordinate cellular metabolism with protein synthesis via specialized translation factors to promote survival in the mammalian gut.
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http://dx.doi.org/10.1128/mBio.03221-19DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6989115PMC
January 2020

Mechanistic Insights into the Effect of Ligands on Structural Stability and Selectivity of Sulfotransferase 2A1 (SULT2A1).

ACS Omega 2019 Dec 10;4(26):22021-22034. Epub 2019 Dec 10.

Key Laboratory for Molecular Enzymology and Engineering of Ministry of Education, School of Life Science, Jilin University, 2699 Qianjin Street, Changchun 130012, China.

Cytosolic sulfotransferases (SULTs) acting as phase II metabolic enzymes can be used in the sulfonation of small molecules by transferring a sulfonate group from the unique co-factor 3'-phosphoadenosine 5'-phosphosulfate (PAPS) to the substrates. In the present study, molecular dynamics (MD) simulations and ensemble docking study were employed to theoretically characterize the mechanism for the effect of co-factor (PAP) and ligands (LCA, raloxifene, α-hydroxytamoxifen, ouabain, and 3'-phosphoadenylyl sulfate) on structural stability and selectivity of SULT2A1 from the perspective of the dynamic behavior of SULT2A1 structures. Structural stability and network analyses indicated that the cooperation between PAP and LCA may enhance the thermal stability and compact communication in enzymes. During the MD simulations, the obviously rigid region and inward displacement were detected in the active-site cap (loop16) of the conformation containing PAP, which may be responsible for the significant changes in substrate accessibility and catalytic activity. The smaller substrates such as LCA could bind stably to the active pocket in the presence of PAP. However, the substrates or inhibitors with a large spatial structure needed to bind to the open conformation (without PAP) prior to PAPS binding.
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http://dx.doi.org/10.1021/acsomega.9b03136DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6933797PMC
December 2019

The formation mechanism of a sea cucumber ovum derived heptapeptide-calcium nanocomposite and its digestion/absorption behavior.

Food Funct 2019 Dec;10(12):8240-8249

National Engineering Research Center of Seafood, School of Food Science and Technology, Dalian Polytechnic University, Dalian 116034, P. R. China.

Asn-Asp-Glu-Glu-Leu-Asn-Lys (NDEELNK), derived from a sea cucumber ovum, has shown a prominent calcium-binding ability. In this study, the formation mechanism of a NDEELNK-calcium nanocomposite and its digestion and absorption behavior were investigated. Results indicated that calcium ions specifically bound to two carboxyl oxygen atoms of Asp and Glu on the NDEELNK peptide in its monomeric form, and that the binding mode was referred to as the "bidentate" mode. Calcium coordination induced the self-assembly of the NDEELNK peptide dominated by an α-helix and a random coil structure, resulting in the formation of nanoparticles with a crystal structure. NDEELNK possessed a good digestive stability of 90.21 ± 1.11% in the gastrointestinal (GI) tract; moreover, two other fragments (DEELNK and EELNK) and seven modified variants were identified by nano-LC-ESI-MS/MS in the GI digests. Nevertheless, the GI digests of the NDEELNK-calcium complex could significantly enhance calcium absorption across the Caco-2 cell monolayers as compared to the initial complex.
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http://dx.doi.org/10.1039/c9fo01335kDOI Listing
December 2019

A comparable method to Gd-contrast enhancement in the preoperative evaluation of anal fistula.

Medicine (Baltimore) 2019 Nov;98(44):e17807

Affiliated Hospital of Shandong University of Traditional Chinese Medicine, Jinan, Shandong.

To explore a comparable method to Gd-contrast enhancement in the preoperative evaluation of anal fistula to evaluate its morphology changes.Forty-six patients with anal fistula were enrolled. Each patient acquired a 3.0T magnetic resonance imaging (MRI) routine sequence, diffusion-weighted imaging (DWI) sequence and fat suppression T1 weighted imaging (FS T1WI) contrast enhancement (CE) scanning. To record the morphology performances of the internal orifice and the fistulas on the transverse images of fat suppression T2 weighted imaging (FS T2WI), DWI, FS T2WI combined with DWI, FS T1WI Gd-CE, with the standard of the surgical pathology results. Two observers evaluated images in consensus. The conspicuity and the diagnostic performance rate were compared between the 4 imaging data sets.The consistencies of interobservers about the conspicuity scores and the diagnostic performance rates of the internal orifice and the fistula were good. The conspicuity of the internal orifice was higher for the set of FS T2WI, FS T2WI+DWI, and FS T1WI+CE than DWI. The diagnostic performance rate of the internal orifice was higher for the set of FS T2WI, FS T2WI+DWI, and FS T1WI+CE than DWI. The conspicuity of the fistula was higher for the set of FS T2WI+DWI and FS T1WI+CE than FS T2WI or DWI. There were no significantly differences between the 4 sets of FS T2WI, DWI, FS T2WI+DWI, and FS T1WI+CE in the diagnostic performance rate of the fistula.The set of FS T2WI combined with DWI was comparable to FS T1WI CE in evaluation of anal fistula morphology changes.
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http://dx.doi.org/10.1097/MD.0000000000017807DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6946531PMC
November 2019

How oncogenic mutations activate human MAP kinase 1 (MEK1): a molecular dynamics simulation study.

J Biomol Struct Dyn 2020 Aug 6;38(13):3942-3958. Epub 2019 Nov 6.

Key Laboratory for Molecular Enzymology and Engineering of Ministry of Education, School of Life Science, Jilin University, Changchun, China.

Approximately 30% of all types of human cancers possess a constitutively activated the mitogen-activated protein kinase (MAPK) signaling pathway while MAP kinase 1 (MEK1) is a critical component of this pathway. It has been reported mutations could improve the activity of MEK1 to result in cell proliferation and transformation, which is a known oncogenic event in various cancer types. In this study, eight molecular dynamics simulations, molecular mechanics Poisson-Boltzmann surface area (MM-PBSA), combined with protein structure network were performed to explore the mechanism that mutations activate MEK1. Protein structure networks and hydrogen bonds analysis demonstrated that active mutations broke the interaction between activation segments (residues 216-222) and C-helix (residues 105-121) in MEK1, leading to it transform inactive form to active form. Moreover, hydrogen bond analysis and MM-PBSA calculation indicated that activating mutations decrease the binding affinity between MEK1 and inhibitor to reduce the inhibitory effect of inhibitors. In addition, some active mutations cause structural changes in the Pro-rich loop (residues 261-268) of MEK1. These changes may stabilize the interaction between the MEK1 mutants and the ligands by increasing the number of exposed hydrophobic residues in the active site of MEK1. Our results may provide useful theoretical evidences for the mechanism underlying the role of human MEK1 in human cancers.Communicated by Ramaswamy H. Sarma.
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http://dx.doi.org/10.1080/07391102.2019.1686065DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8177546PMC
August 2020

Calcium Delivery System Assembled by a Nanostructured Peptide Derived from the Sea Cucumber Ovum.

J Agric Food Chem 2019 Nov 24;67(44):12283-12292. Epub 2019 Oct 24.

National Engineering Research Center of Seafood, School of Food Science and Technology , Dalian Polytechnic University , Dalian 116034 , P. R. China.

In this study, the binding mechanism, morphological, and conformational analysis of the complex of a sea cucumber ovum derived octapeptide (EDLAALEK) with Ca as well as its calcium delivery behavior via the gastrointestinal (GI) tract were investigated. The Ca specifically bound to two carboxyl oxygen atoms of C-terminal Glu and Asp on the EDLAALEK peptide at a stoichiometric ratio of 1:1. Calcium coordination induced the self-assembly of the EDLAALEK peptide, resulting in the formation of a nanocomposite with a crystal structure. Furthermore, the formed nanocomposite went through dissociation and self-assembly during in vitro GI digestion, accompanied by the release and rechelation of Ca, which was related to changes in their secondary structure. Nevertheless, the GI digests of the EDLAALEK-calcium complex could significantly enhance Ca absorption across Caco-2 cell monolayers. The findings suggest that the sea cucumber ovum derived peptide has the potential as an efficient nanocarrier to transport calcium through the GI system.
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http://dx.doi.org/10.1021/acs.jafc.9b04522DOI Listing
November 2019

Iodine-124 Labeled Gold Nanoclusters for Positron Emission Tomography Imaging in Lung Cancer Model.

J Nanosci Nanotechnol 2020 03;20(3):1375-1382

Beijing Engineering Research Center of Radiographic Techniques and Equipment, Institute of High Energy Physics, Chinese Academy of Sciences, Beijing 100049, China.

This work reports the synthesis, radiolabeling and imaging studies of iodine-124 labeled peptide modified gold nanoclusters (AuNCs) as positron emission tomography (PET) tracer for lung cancer. The novel modified Au nanoclusters were successfully synthesized by conjugation of tumortargeting peptide luteinizing hormone releasing hormone (LHRH) to human serum albumin (HAS) as a scaffold, resulting in 73% labeling yield of 124I-LHRH-HSA AuNCs. After rapid purification, the radiochemical purity was above 98%. Dynamic PET study in normal rats showed high liver accumulation and rapid lung clearance. Both the PET and fluorescence imaging in A549 xenografted tumor model demonstrated certain amount of tumor uptake. In orthotopic lung cancer model, the tumor sites could be clearly visualized between 2 to 5 hours in PET images. The higher radioactivity concentration in the left lung which inoculated orthotopic tumor than right lung also exhibited the targeting properties. The biological properties of this iodine-124 labeled nanoclusters afford potential applications for early diagnosis of lung cancer with PET.
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http://dx.doi.org/10.1166/jnn.2020.17169DOI Listing
March 2020

Decreased 25-Hydroxyvitamin D Levels in Patients With Vestibular Neuritis.

Front Neurol 2019 8;10:863. Epub 2019 Aug 8.

Department of Neurology, Hwa Mei Hospital, University of Chinese Academy of Science, Ningbo, China.

Vestibular neuritis (VN) is characterized by acute onset of vertigo, nausea, and vomiting, without auditory or other neurological symptoms. Although the pathogenesis of VN is not yet clear, many studies have shown that a pro-inflammatory environment can lead to the induction and progression of the disease. Considering the importance of vitamin D in modulating the activation, proliferation, and differentiation of inflammatory physiological processes, we hypothesized that decreased serum vitamin D may be associated with the development of VN. In this study, we evaluated serum levels of 25-hydroxyvitamin D [25(OH)D] in patients presenting acutely with VN and healthy controls and investigated the possible correlation of serum 25(OH)D levels with VN. A total of 59 consecutive patients diagnosed with VN within 7 days of symptom onset and 112 age- and sex-matched healthy controls referred to Hwa Mei Hospital, University of Chinese Academy of Science, between March 2017 and March 2019 were recruited. Demographic and clinical data, such as age, sex, height, weight, living habits, ongoing health problems, and medication history, for all subjects were recorded, and levels of 25(OH)D were measured and compared. Serum levels of 25(OH)D were lower in patients with VN than in controls (19.01 ± 6.53 vs. 22.94 ± 6.74 ng/ml, < 0.001). Patients with VN had a higher frequency of vitamin D deficiency (61.0 vs. 34.8%, = 0.001) than did controls. Regression analyses demonstrated that vitamin D deficiency was associated with VN, with an odds ratio of 4.53 (95% CI = 1.342-15.279, = 0.015). This prospective study is the first to evaluate serum 25(OH)D levels in patients with VN and found that decreased serum 25(OH)D may be associated with VN occurrence.
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http://dx.doi.org/10.3389/fneur.2019.00863DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6694755PMC
August 2019

Exploration of Catalytic Selectivity for Aminotransferase (BtrR) Based on Multiple Molecular Dynamics Simulations.

Int J Mol Sci 2019 Mar 8;20(5). Epub 2019 Mar 8.

Key Laboratory for Molecular Enzymology and Engineering of the Ministry of Education, National Engineering Laboratory of AIDS Vaccine, College of Life Science, Jilin University, Changchun 130023, China.

The aminotransferase from (BtrR), which is involved in the biosynthesis of butirosin, catalyzes the pyridoxal phosphate (PLP)-dependent transamination reaction to convert valienone to β-valienamine (a new β-glycosidase inhibitor for the treatment of lysosomal storage diseases) with an optical purity enantiomeric excess value. To explore the stereoselective mechanism of valienamine generated by BtrR, multiple molecular dynamics (MD) simulations were performed for the BtrR/PLP/valienamine and BtrR/PLP/β-valienamine complexes. The theoretical results showed that β-valienamine could make BtrR more stable and dense than valienamine. β-valienamine could increase the hydrogen bond probability and decrease the binding free energy between coenzyme PLP and BtrR by regulating the protein structure of BtrR, which was conducive to the catalytic reaction. β-valienamine maintained the formation of cation-p interactions between basic and aromatic amino acids in BtrR, thus enhancing its stability and catalytic activity. In addition, CAVER 3.0 analysis revealed that β-valienamine could make the tunnel of BtrR wider and straight, which was propitious to the removal of products from BtrR. Steered MD simulation results showed that valienamine interacted with more residues in the tunnel during dissociation compared with β-valienamine, resulting in the need for a stronger force to be acquired from BtrR. Taken together, BtrR was more inclined to catalyze the substrates to form β-valienamine, either from the point of view of the catalytic reaction or product removal.
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http://dx.doi.org/10.3390/ijms20051188DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6429434PMC
March 2019

Insights from molecular dynamics simulations and steered molecular dynamics simulations to exploit new trends of the interaction between HIF-1α and p300.

J Biomol Struct Dyn 2020 01 4;38(1):1-12. Epub 2019 Mar 4.

Key Laboratory for Molecular Enzymology and Engineering of the Ministry of Education, School of Life Science, Jilin University, Changchun, China.

Hypoxia-inducible factor-1 (HIF-1) is a transcription factor that plays an important role in the expression of genes, whose function is exerted through protein-protein interactions (PPIs), such as the transcriptional co-activator (CREB)-binding protein (CBP) and p300. Under hypoxic conditions, HIF-1is stabilized and translocated to CBP or p300, leading to the hypoxic response cascade. Furthermore, the PPI between HIF and p300/CBP is a potential cancer target for their role in the hypoxic response. In this study, molecular dynamics (MD) simulation was used to explore the conformational change for the p300 binding to one subunit of HIF-1, namely HIF1α. Results indicated that HIF-1α-p300 complex was stable during MD simulation. New H-bonds were made in the intra-chain of p300 with HIF-1α binding. Inhibiting the HIF-1α-p300 interaction modulated the HIF-1α identification of selective molecules, which may indicate the target metabolic and cellular processes that enable the survival and growth of tumors in cancer chemotherapy. CAVER 3.0 results suggested that three main tunnels were present, according to helices 1, 2 and 3 of p300. To explore the unbinding pathway for HIF-1α via p300, we selected helices 1, 2 and 3 on the HIF-1α as a new ligand to explore the unbinding pathway via its own tunnel. For helix 1, R368 in p300 formed a H-bond with E816 in HIF1-α. A345 and D346 in p300 formed H-bonds with N803 in HIF-1α. A H-bond existed between K351(p300) and E789 (Hif1-α). These molecules may be the key residues in the unbinding pathway via its tunnel.Communicated by Ramaswamy H. Sarma.
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http://dx.doi.org/10.1080/07391102.2019.1580616DOI Listing
January 2020

Dietary sugar silences a colonization factor in a mammalian gut symbiont.

Proc Natl Acad Sci U S A 2019 01 17;116(1):233-238. Epub 2018 Dec 17.

Department of Microbial Pathogenesis, Yale School of Medicine, New Haven, CT 06536;

The composition of the gut microbiota is largely determined by environmental factors including the host diet. Dietary components are believed to influence the composition of the gut microbiota by serving as nutrients to a subset of microbes, thereby favoring their expansion. However, we now report that dietary fructose and glucose, which are prevalent in the Western diet, specifically silence a protein that is necessary for gut colonization, but not for utilization of these sugars, by the human gut commensal Silencing by fructose and glucose requires the 5' leader region of the mRNA specifying the protein, designated Roc for regulator of colonization. Incorporation of the leader mRNA in front of a heterologous gene was sufficient for fructose and glucose to turn off expression of the corresponding protein. An engineered strain refractory to Roc silencing by these sugars outcompeted wild-type in mice fed a diet rich in glucose and sucrose (a disaccharide composed of glucose and fructose), but not in mice fed a complex polysaccharide-rich diet. Our findings underscore a role for dietary sugars that escape absorption by the host intestine and reach the microbiota: regulation of gut colonization by beneficial microbes independently of supplying nutrients to the microbiota.
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http://dx.doi.org/10.1073/pnas.1813780115DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6320540PMC
January 2019

Effects of Tyr555 and Trp678 on the processivity of cellobiohydrolase A from Ruminiclostridium thermocellum: A simulation study.

Biopolymers 2018 Dec 28;109(12):e23238. Epub 2018 Nov 28.

Laboratory of Theoretical and Computational Chemistry, Institute of Theoretical Chemistry, Jilin University, Changchun, China.

Cellobiohydrolase A from Ruminiclostridium thermocellum (Cbh9A) is a processive exoglucanase from family 9 and is an important cellobiohydrolase that hydrolyzes cello-oligosaccharide into cellobiose. Residues Tyr555 and Trp678 considerably affect catalytic activity, but their mechanisms are still unknown. To investigate how the Tyr555 and Trp678 affect the processivity of Cbh9A, conventional molecular dynamics, steered molecular dynamics, and free energy calculation were performed to simulate the processive process of wild type (WT)-Cbh9A, Y555S mutant, and W678G mutant. Analysis of simulation results suggests that the binding free energies between the substrate and WT-Cbh9A are lower than those of Y555S and W678G mutants. The pull forces and energy barrier in Y555S and W678G mutants also reduced significantly during the steered molecular dynamics (SMD) simulation compared with that of the WT-Cbh9A. And the potential mean force calculations showed that the pulling energy barrier of Y555S and W678G mutants is much lower than that of WT-Cbh9A.
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http://dx.doi.org/10.1002/bip.23238DOI Listing
December 2018

Probing inhibition mechanisms of adenosine deaminase by using molecular dynamics simulations.

PLoS One 2018 16;13(11):e0207234. Epub 2018 Nov 16.

Key Laboratory for Molecular Enzymology and Engineering of the Ministry of Education, School of Life Science, Jilin University, Changchun, China.

Adenosine deaminase (ADA) catalyzes the deamination of adenosine, which is important in purine metabolism. ADA is ubiquitous to almost all human tissues, and ADA abnormalities have been reported in various diseases, including rheumatoid arthritis. ADA can be divided into two conformations based on the inhibitor that it binds to: open and closed forms. Here, we chose three ligands, namely, FR117016 (FR0), FR221647 (FR2) (open form), and HDPR (PRH, closed form), to investigate the inhibition mechanism of ADA and its effect on ADA through molecular dynamics simulations. In open forms, Egap and electrostatic potential (ESP) indicated that electron transfer might occur more easily in FR0 than in FR2. Binding free energy and hydrogen bond occupation revealed that the ADA-FR0 complex had a more stable structure than ADA-FR2. The probability of residues Pro159 to Lys171 of ADA-FR0 and ADA-FR2 to form a helix moderately increased compared with that in nonligated ADA. In comparison with FR0 and FR2 PRH could maintain ADA in a closed form to inhibit the function of ADA. The α7 helix (residues Thr57 to Ala73) of ADA in the closed form was mostly unfastened because of the effect of PRH. The number of H bonds and the relative superiority of the binding free energy indicated that the binding strength of PRH to ADA was significantly lower than that of an open inhibitor, thereby supporting the comparison of the inhibitory activities of the three ligands. Alanine scanning results showed that His17, Gly184, Asp295, and Asp296 exerted the greatest effects on protein energy, suggesting that they played crucial roles in binding to inhibitors. This study served as a theoretical basis for the development of new ADA inhibitors.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0207234PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6239307PMC
April 2019