scholarly journals Combination of pharmacophore hypothesis and molecular docking to identify novel inhibitors of HCV NS5B polymerase

2015 ◽  
Vol 19 (3) ◽  
pp. 529-539 ◽  
Author(s):  
Amaravadhi Harikishore ◽  
Enlin Li ◽  
Jia Jun Lee ◽  
Nam-Joon Cho ◽  
Ho Sup Yoon
Keyword(s):  
Molecular Docking ◽  
Pharmacophore Hypothesis ◽  
Hcv Ns5b ◽  
Ns5b Polymerase

Molecular docking and Pharmacoinformatics studies reveal potential phytochemicals against HCV NS5B Polymerase

2020 ◽  
Vol 23 ◽  
Author(s):  
Hina Khalid ◽  
Usman Ali Ashfaq
Keyword(s):  
Molecular Docking ◽  
Computational Study ◽  
Health Issues ◽  
Reference Drug ◽  
Antiviral Compounds ◽  
Alternative Approach ◽  
Study Results ◽  
Docking Approach ◽  
Hcv Ns5b ◽  
Ns5b Polymerase

: Background: Hepatitis C Virus (HCV) is one of the serious health issues affecting one-third of the world’s population. The high variations of the HCV genome are ascribed to quick replication by NS5B Polymerase and are thus the most attractive target for developing anti-HCV agents. Objective: The current study aimed to discover novel phytochemicals that harbor the potential of NS5B polymerase inhibition. Method: In this computational study, a molecular docking approach was used to screen phytochemicals with the best binding and spatial affinity with NS5B at the Palm I region. The top-ranked compounds were then subjected to in-silico pharmacokinetic and toxicological study. Results and Conclusion: The virtual screening provided seven ‘hit compounds’ including Betanin, 3,5'- dihydroxythalifaboramine, Diarctigenin, 6'-desmethylthalifaboramine, Cephalotaxine, 5alpha-O-(3'-dimethylamino-3'- phenylpropionyl) taxinine M and IsoTetrandrine with minimum binding score compared to the reference drug, Sofosbuvir (−14.7 kcal/mol). The absorption, distribution, metabolism, excretion, and toxicity (ADMET) and thorough toxicological analysis revealed a favorable and the safety profile of these compounds. The study would demonstrate the phytochemicals identified might serve as potential antiviral compounds that can potentially an alternative approach for amelioration of HCV

QSAR and Molecular Docking Directed Synthesis and Preliminary Evaluation of Novel Non-Nucleoside HCV NS5B Polymerase Inhibitors

2017 ◽  
Vol 15 (1) ◽  
pp. 52-56
Author(s):  
Vaishali M. Patil ◽  
Neeraj Masand ◽  
Gurukumar K. R ◽  
Maksim Chudayeu ◽  
Satya Prakash Gupta ◽  
...  
Keyword(s):  
Molecular Docking ◽  
Preliminary Evaluation ◽  
Polymerase Inhibitors ◽  
Directed Synthesis ◽  
Hcv Ns5b ◽  
Ns5b Polymerase

Repositioning of RdRp Inhibitors against HCV NS5B Polymerase Utilizing Structure-Based Molecular Docking

2021 ◽  
Vol 24 ◽  
Author(s):  
Heena Tarannum ◽  
Sisir Nandi
Keyword(s):  
Molecular Docking ◽  
Hepatitis C ◽  
Yellow Fever ◽  
Yellow Fever Virus ◽  
Docking Simulation ◽  
World Health ◽  
Reference Drug ◽  
The World ◽  
Hcv Ns5b ◽  
Ns5b Polymerase

Objective: Hepatitis C Virus (HCV) is very dreadful as it can attack an estimated 71 million people around the world. The World Health Organization (WHO) reported that every year about 399000 people die due to HCV caused by chronic cirrhosis and liver cancer globally. There are many drugs available for the treatment of HCV. But drug resistance and toxicity are major issues. The quest for potential drugs utilizing repositioning would be a very useful and economical method to combat the HCV. Methods: One of the most HCV targets is RNA dependent RNA polymerase (RdRp). The RdRp is common in HCV, Dengue virus (DENV), Zika virus (ZIKV), and Yellow fever virus (YFV) belonging to the same family of Flaviviridae. An attempt has been made in the present study to repositioning different DENV, ZIKV, and YFV RdRp inhibitors against HCV NS5B polymerase utilizing structure-based molecular docking which explores the affinity and mode of binding of these RdRp inhibitors. Results: Several 87 compounds having dengue, yellow fever and zika RdRp inhibitory activities have been taken into consideration for the screening of potential RdRp leads utilizing docking simulation which focuses the affinity and mode of binding of sofosbuvir diphosphate which is a standard HCV, RdRp inhibitor. Conclusion: It was found that the compounds 6 (N-sulfonylanthranilic acid derivative), 17 (R1479), 20 (DMB220), 23 (FD-83-KI26), 40 (CCG-7648), 50 (T-1106), 65 (mycophenolic acid), and 69 (DMB213) can produce docking score with the range of -7.602 to -8.971 Kcal/Mol having almost same mode of interaction as compared to the reference drug molecule. The drugs mentioned above can produce satisfactory affinity to bind the hepatitis C viral RdRp and thus may be used to treat the disease. Therefore, these predicted compounds may be potential leads for further testing of anti HCV activity and can be repurposed to combat HCV. The high throughput shotgun of drug repurposing utilizing structure-based docking simulation freeware would be a cost-effective way to screen the potential anti-HCV leads.

Novel Guanosine Derivatives as Anti-HCV NS5b Polymerase: A QSAR and Molecular Docking Study

2019 ◽  
Vol 15 (2) ◽  
pp. 130-137 ◽  
Author(s):  
Abdo A. Elfiky
Keyword(s):  
Molecular Docking ◽  
Binding Affinity ◽  
Active Site ◽  
Docking Study ◽  
Binding Affinities ◽  
Molecular Docking Study ◽  
Docking Calculations ◽  
Quantitative Structure Activity Relationships ◽  
Hcv Ns5b ◽  
Ns5b Polymerase

Background: IDX-184 is a guanosine derivative having a potent inhibitory performance against HCV NS5b polymerase. Objective: To test three different groups of 2'C - modified analogues of guanosine nucleotide against HCV polymerase. Method: Using combined Quantitative Structure-Activity Relationships (QSAR) and molecular docking, the suggested compounds are studied. Results: Examining the docked structures of the compounds with experimentally solved NS5b structure (PDB ID: 2XI3) revealed that most of the compounds have the same mode of interaction as that of guanosine nucleotide and hence, NS5b inhibition is possible. Conclusion: It is revealed that sixteen modifications have a better binding affinity to NS5b compared to guanosine. In addition, seven more compounds are better in NS5b binding compared to the approved drug, sofosbuvir, and the compound under clinical trials, IDX-184. Hence, these compounds could be potent HCV NS5b inhibitors. Summary Points: Novel guanosine modifications were introduced in silico and optimized using QM. QSAR and docking calculations are performed to test the binding affinity of the compounds to HCV NS5b active site. Comparison between the binding affinities and the mode of interactions of the compounds and both GTP and IDX-184 is performed. Structural mining to quantify the mode of binding of the compounds to NS5b active site pocket.

Combined 3D-QSAR, molecular docking and molecular dynamics study on the benzimidazole inhibitors targeting HCV NS5B polymerase

2019 ◽  
Vol 38 (4) ◽  
pp. 1071-1082 ◽  
Author(s):  
Zhiguo Wang ◽  
Zhenming Chen ◽  
Jianfeng Li ◽  
Jing Huang ◽  
Chenni Zheng ◽  
...  
Keyword(s):  
Molecular Dynamics ◽  
Molecular Docking ◽  
3D Qsar ◽  
Hcv Ns5b ◽  
Ns5b Polymerase

scholarly journals Molecular modeling study on the drug resistance mechanism of NS5B polymerase to TMC647055

2016 ◽  
Vol 94 (2) ◽  
pp. 147-158 ◽  
Author(s):  
Huiqun Wang ◽  
Wei Cui ◽  
Chenchen Guo ◽  
Bo-Zhen Chen ◽  
Mingjuan Ji
Keyword(s):  
Drug Resistance ◽  
Free Energy ◽  
Rational Design ◽  
Binding Free Energy ◽  
Resistance Mechanism ◽  
Free Energy Calculations ◽  
Side Chain ◽  
Free Energy Decomposition ◽  
Hcv Ns5b ◽  
Ns5b Polymerase

NS5B polymerase plays an important role in viral replication machinery. TMC647055 (TMC) is a novel and potent non-nucleoside inhibitor of the HCV NS5B polymerase. However, mutations that result in drug resistance to TMC have been reported. In this study, we used molecular dynamics (MD) simulations, binding free energy calculations, and free energy decomposition to investigate the drug resistance mechanism of HCV to TMC resulting from L392I, P495T, P495S, and P495L mutations in NS5B polymerase. From the calculated results we determined that the decrease in the binding affinity between TMC and NS5BL392I polymerase is mainly caused by the extra methyl group at the CB atom of Ile. The polarity of the side-chain of residue 495 has no distinct influence on residue 495 binding with TMC, whereas the smaller size of the side-chain of residue 495 causes a substantial decrease in the van der Walls interaction between TMC and residue 495. Moreover, the longer length of the side-chain of residue 495 has a significant effect on the electrostatic interaction between TMC and Arg-503. Finally, we performed the same calculations and detailed analysis on other 3 mutations (L392V, P495V, and P495I). The results further confirmed our conclusions. The computational results not only reveal the drug resistance mechanism between TMC647055 and NS5B polymerase, but also provide valuable information for the rational design of more potent non-nucleoside inhibitors targeting HCV NS5B polymerase.

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