Insight into the Structural Requirements of Benzothiadiazine Scaffold-Based Derivatives as Hepatitis C Virus NS5B Polymerase Inhibitors Using 3D-QSAR, Molecular Docking and Molecular Dynamics

Abstract

Hepatitis C virus (HCV) infection is a significant world health threat with frequently ineffective problem existed in the present treatment, thus representing a major unmet medical need. The nonstructural viral protein 5B (NS5B), one of the best-studied polymerase, has emerged as an attractive target for the development of novel therapeutics against hepatitis C virus. In this work, both ligand- and receptor- based three-dimensional quantitative structure activity relationship (3D-QSAR) studies were carried out using comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) techniques on 360 benzothiadiazine scaffold-based derivatives as HCV GT-1b NS5B polymerase allosteric inhibitors. The resultant optimum 3D-QSAR model exhibited R(2)(ev) of 0.54, R(2)(nev) of 0.72 and the predictive ability was validated by using an independent test set of 90 compounds which gave R(2)(pred) value of 0.64. In addition, docking analysis and molecular dynamics simulation (MD) were also applied to elucidate the probable binding modes of these inhibitors at the allosteric site of the enzyme. Interpretation of the 3D contour maps in context of the topology of the allosteric binding site of NS5B provided insight into NS5B-inhibitor interactions. The information obtained from this work can be utilized to accurately predict the binding affinity of related analogues and also facilitate the future rational design of novel inhibitors with improved activity.

A System-Level Investigation into the Mechanisms of Chinese Traditional Medicine: Compound Danshen Formula for Cardiovascular Disease Treatment

“…Finally, to the most extent 320 compounds were collected, including 201 in Radix Salviae Miltiorrhizae , 112 in Panax Notoginseng and 31 in Borneolum , respectively (The three herbal shared the same 24 compounds). The structures of these molecules were downloaded from LookChem (www.lookchem.com) or produced by ISIS Draw 2.5 (MDL Information Systems, Inc.) and further optimized by Sybyl 6.9 (Tripos, Inc) with sybyl force field and default parameters [22], [23]. The molecules were saved to a mol format for further analysis.…”

TBC2target: A Resource of Predicted Target Genes of Tea Bioactive Compounds

“…For these TBCs, a chemist manually produced their 3D structures using ISIS Draw 1 (MDL Information Systems, Inc.) by referring to the original articles. The 3D structures of TBCs were optimized in Sybyl 2 (Tripos, Inc.) using the standard Tripos force field ( Zhang et al, 2011 ).…”

TBC2health: a database of experimentally validated health-beneficial effects of tea bioactive compounds

“…Using original publications, we manually produced the structures of TBCs documented in TBC2health using ISIS Draw (MDL Information Systems, Inc.). Structures of TBCs were further optimized by Sybyl (Tripos, Inc), with sybyl force field and default parameters [ 28 ]. All the TBC structures in mol2, SDF and PDB formats were made accessible for users to facilitate several useful applications, such as molecular docking, dynamic simulation and drug design.…”