Philippine Journal of Science
147 (1): 37-46, March 2018
ISSN 0031 – 7683
Date Received: 24 Apr 2017

In silico Studies on N- (Pyridin-2-yl) Thiobenzamides as NNRTIs against Wild and Mutant HIV-1 Strains

Anuradha Singh, Vishal Kumar Singh, Rajesh Verma, and Ramendra K. Singh*

Bioorganic Research Laboratory, Department of Chemistry,
University of Allahabad, Allahabad-211002, India

*Corresponding author: rksinghsrk@gmail.com

ABSTRACT

In the present study, keeping the Lipinski’s Rule of Five in focus, a series of new 4-(4-benzenesulfonylamino)-N-(5-substituted-pyridin-2-yl)-thiobenzamides bearing different substituents at the C-4 position of benzenesulfonylamino ring have been designed as NNRTIs of wild-type (WT) and mutant HIV-1 strains. Molecules having drug-like character were further docked into the active domain of wild-type (WT) RT/1 with entry code (PDB: ID 3mec) and K103N/TYR181 mutant RT/2 complex (PDB: ID 3BGR) using Discovery Studio 2.5 software. Analysis of the docking results revealed that all molecules formed hydrogen bonds with active amino acids (Lys101, Lys103, Tyr181, and Tyr318) and exhibited π-stacking interactions with Tyr181, Tyr188, Phe227, and Trp229 present in the NNIBP with both WT and mutant HIV-1 RT. The designed ligands adopted ‘horseshoe/seahorse’ conformation inside the NNIBP like other second generation NNRTIs and formed more stable complexes (total interaction energy found in the range of (-) 54 – (-) 77 kcal/mol) with HIV-1 RT in comparison to etravirine and rilpivirine (-)61.43 and (-)50.23 Kcal/mol, respectively. Consequently, lower EC50 values were predicted for N- (Pyridin-2-yl) derivatives. Structure-activity relationships (SARs) are discussed in terms of a possible interaction with the RT binding site, depending on the nature of the substituent at ring A and ring C.