In silico evaluation of molecular interactions between macrocyclic inhibitors with the HCV NS3 protease. Docking and identification of antiviral pharmacophore site

Abstract

An array of computational approaches DFT/QSAR/POM methods has been used for a better understanding of drug properties regarding 13 inhibitor derivatives containing either P2 cyclopentane P1 carboxylic acid moiety (1-9) or a P1 cyclopropyl acyl sulfonamide (10-13). To further recognize binding interactions and their activity trends, molecular docking studies were carried out with the use of HCV, which can be used to accurately predict the interactions of ligands with the receptor. The QSAR models are developed through the use of Multiple Linear Regression (MLR) together with Principal Component Analysis (PCA) methods. The statistical results indicate the multiple correlation coefficient R² = 0.840, which shows favorable estimation stability, as well as showing a significant correlation between the HCV NS3 protease of the studied compounds and their electron-accepting ability. The POM analysis of the Physico-chemical properties of compounds 1-13, shows that they are bearing (O1, O2) and/or (O1, O2, O3) antiviral pockets, whereby all oxygen atoms are Osp2 and bearing negative charges. Similar to the reference ligand (F9K), the most active compound 10 was bound deeply into the binding cavity of NS3 protease making interactions with the residues Gly137, His57, Ala157, and His528. The anti-hepatitis pharmacophore site is similar to the anti-HIV pharmacophore site.

Communicated by Ramaswamy H. Sarma

The aim of this study is to evaluate molecular interactions for macrocyclic cyclopentane inhibitors with the HCV inhibitory and to identify the antiviral pharmacophore site. The POM analysis of the Physico-chemical properties of all synthesized compounds shows that they are bearing (O1, O2) and/or (O1, O2, O3) antiviral pockets, whereby all oxygen atoms are Osp², and bearing negative charges. The anti-hepatitis pharmacophore site is similar to the anti-HIV pharmacophore site.

Keywords:

• Hepatitis C virus
• NS3/4A serine protease
• DFT
• QSAR
• molecular docking
• POM (Petra/Osiris/Molinspiration) analyses
• Antiviral pharmacophore site identification

Acknowledgments

The authors would like to thank the Deanship of Scientific Research at Umm Al-Qura University for supporting this work by Grant Code: (20UQU0044DSR). We also thank The General Directorate for Scientific Research and Technological Development (DG-RSDT), the Algerian Ministry of Scientific Research.

Disclosure statement

No potential conflict of interest was reported by the authors.