Computational insight to design new potential hepatitis C virus NS5B polymerase inhibitors with drug-likeness and pharmacokinetic ADMET parameters predictions

Background Hepatitis C virus (HCV) is considered a worldwide health problem since it affects over 3% of the population and causes 300,000 fatalities per year. Chronic infection causes high morbidity and mortality in patients, leading to liver cirrhosis, hepatocellular carcinoma, fibrosis, liver cancer, and other HCV-related illnesses. Finding novel and better HCV treatments is a top international health goal right now. As a result, the pressing need for new HCV antiviral drugs has fueled research into the structural requirements of NS5B polymerase inhibitors at a molecular basis. Results In this study, an in silico technique was applied to study 79 compounds with HCV inhibitory bioactivity, with the best statistical results ($$R^{2}$$ R 2 = 0.7051, $$Q^{2}$$ Q 2 = 0.6455, $$R_{{{\text{pred}}}}^{2}$$ R pred 2 = 0.6992, $$^{{\text{c}}} R_{{\text{r}}}^{2}$$ c R r 2 = 0.6570, SEE = 0.2694). Conclusions This QSAR investigation allowed the research team to evaluate the influence of straightforward descriptors, shedding insight into the critical elements that guide the design of innovative effective molecules. Most of the innovative effective molecules exhibited better binding affinity (− 195.6 kcal/mol) than dasabuvir the reference drug (− 171.0 kcal/mol) with the target receptor (hepatitis C virus NS5B RNA polymerase). ADMET prediction disclosed enhanced pharmacokinetic properties with lower MRTD (maximum tolerated dose) of some new derivatives.

Topomer CoMFA, HQSAR Study of Benzimidazole Derivative as NS5B Polymerase Inhibitor

Background: In recent years, the number of people infected with hepatitis C virus (HCV) has continued to grow, this becoming a major threat to global health, and new anti-HCV drugs are urgently needed. HCV NS5B polymerase is an RNA-dependent RNA polymerase (RdRp), which plays an important role in virus replication, and can effectively prevent the replication of HCV sub-genomic RNA in daughter cells. It is considered a very promising HCV therapeutic target for the design of anti-HCV drugs. Methods: In order to explore the relationship between the structure of benzimidazole derivatives and its inhibitory activity on NS5B polymerase, holographic quantitative structure-activity relationship (HQSAR) and Topomer comparative molecular field analysis (CoMFA) were used to establish benzimidazole QSAR model of derivative inhibitors. Results: The results show that for the Topomer CoMFA model, the cross-validation coefficient q2 value is 0.883, and the non-cross-validation coefficient r2 value is 0.975. The model is reasonable, reliable, and has good predictive ability. For the HQSAR model, the cross-validated q2 value is 0.922, and the uncross-validated r2 value is 0.971, indicating that the model data fits well and has high predictive ability. Through the analysis of contour map and color code diagram, 40 new benzimidazole inhibitor molecules were designed, and all of them have higher activity than template molecules, and the new molecules have significant interaction sites with protein 3SKE. Conclusion: The 3D-QSAR model established by Topomer CoMFA and HQSAR has good prediction results and the statistical verification is valid. The newly designed molecules and docking results provide theoretical guidance for the synthesis of new NS5B polymerase inhibitors, and for the identification of key residues that the inhibitor binds to NS5B, which helps to better understand its inhibitory mechanism. These findings are helpful for the development of new anti-HCV drugs.

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

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.

Molecular docking and Pharmacoinformatics studies reveal potential phytochemicals against HCV 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