Insight into the structural requirements of narlaprevir-type inhibitors of NS3/NS4A protease based on HQSAR and molecular field analyses.
ABSTRACT In the life cycle of hepatitis C virus (HCV), NS3/NS4A protease has been proved to play a vital role in the replication of the HCV virus. Narlaprevir and its derivatives, the inhibitors of NS3/NS4A, would be potentially developed as important anti-HCV drugs in the future. In this study, quantitative structure-activity relationship (QSAR) analyses for 190 narlaprevir derivatives were conducted using comparative molecular field analysis (CoMFA), comparative molecular indices analysis (CoMSIA) and hologram quantitative structure-activity relationship (HQSAR) techniques. Both of the best CoMFA and HQSAR models showed statistical significance for the training set and good predictive accuracy for the test set, which strongly manifested the robustness of the CoMFA and HQSAR models. The CoMFA contour maps and the HQSAR contribution maps were both presented. Furthermore, based on the essential factors for ligand binding derived from the QSAR models, sixteen new derivatives were designed and some of them showed higher inhibitory activities confirmed by our models and molecular docking studies. General speaking, this study provides useful suggestions for the design of potential anti-HCV drugs.
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ABSTRACT: After a decade of having been the standard of care (SOC) for the treatment of chronic HCV infection, PEGylated IFN (combined with ribavirin) is now at the verge of being complemented and then replaced by a combination of new DAAs and even some compounds interacting with host cell factors. Principal targets for the direct-acting antivirals (DAAs) are the protease NS3/4A, the protein NS5A, and the RNA-dependent RNA polymerase NS5B, which offers at least two target sites, the catalytic domain for nucleos(t)ides and several non-catalytic (allosteric) domains for the non-nucleoside type of NS5B inhibitors. Two PIs have already been approved, but many more NS3/4A, NS5A, and NS5B (up to 40!) inhibitors are in (pre)clinical development. The abundance of candidate anti-HCV drugs will, on the one hand, speed up their development but, on the other hand, complicate the choice of the most appropriate drug combination(s). Copyright © 2012 John Wiley & Sons, Ltd.Reviews in Medical Virology 08/2012; · 7.62 Impact Factor