narlaprevir and Hepatitis-C

Hepatitis C virus (HCV) mortality and morbidity is a world health misery with an approximate 130-150 million chronically HCV tainted and suffering individuals and it initiate critical liver malfunction like cirrhosis, hepatocellular carcinoma or liver HCV cancer. HCV NS5B protein one of the best studied therapeutic target for the identification of new drug candidates to be added to the combination or multiple combination medication recently approved. During the past few years, NS5B has thus been an important object of attractive medicinal chemistry endeavors, which induced to the surfacing of betrothal preclinical drug molecules. In this scenario, the current review set limit to discuss research published on NS5B and few other therapeutic functional inhibitors concentrating on hit investigation, hit to lead optimization, ADME parameters evaluation, and the SAR data which was out for each compound type and similarity taken into consideration. The discussion outlined in this specific review will surly helpful and vital tool for those medicinal chemists investigators working with HCV research programs mainly pointing on NS5B and set broad spectrum identification of creative anti HCV compounds. This mini review also tells each and every individual compound ability related how much they are active against NS5B and few other targets.

Topics: Antiviral Agents; Hepacivirus; Hepatitis C; Humans; Polyproteins; Structure-Activity Relationship; Viral Nonstructural Proteins

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.

Topics: Antiviral Agents; Carrier Proteins; Cyclopropanes; Dipeptides; Drug Design; Hepacivirus; Hepatitis C; Humans; Intracellular Signaling Peptides and Proteins; Leucine; Models, Molecular; Proline; Quantitative Structure-Activity Relationship; Sulfones; Urea; Viral Nonstructural Proteins