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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: This email address is being protected from spambots. You need JavaScript enabled to view it.

 

 

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.

 

INTRODUCTION

Kappaphycus alvarezii (Doty ex P.C. Silva 1996) is an introduced-species, which has been mono-cultivated as the largest seaweed commodity not only in Indonesia, but also in other tropical Asian countries. Indonesia is currently leading the production of K. alvarezii with nearly 1.5 x 106 tons in 2009, driven by the increasing demand for κ-carrageenan (Meinita et al. 2012). Another potential seaweed is Padina australis (Hauck 1887), a native species of brown seaweed that is increasingly being cultivated and studied as source of alginate (Widyastuti 2012). In addition to carrageenan and alginate, K. alvarezii and P. australis are also rich sources of natural pigments that have other additional biological functions (i.e., antioxidant, anti-obesity, anti-inflammation, and anti-hyper cholesterol) as well as natural colorants, depending on the chemical properties of the pigment. However, while great interest has been expressed in recent decade to characterize the distribution, biosynthesis, and functions as well as application of the photosynthetic pigments of microalgae, little effort has been dedicated to characterize other pigments in those seaweeds......read more

 

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