IN-SILICO ADMET STUDY AND MOLECULAR DOCKING OF TRIAZOLE- 3-THIONE DERIVATIVES TARGETING LIPOTEICHOIC ACID SYNTHASE IN GRAM-POSITIVE BACTERIA

Abstract

Introduction: Rapid global emergence of antimicrobial resistance led to the failure of many of the antibiotics available in the market. Among multi drug resistant Gram +ve bacteria, methicillin and vancomycin resistant, Staphylococcus aureus strains are leading causes of nosocomial infections involving skin, soft tissues and urinary tract. Therefore, search for new drug targets that are unique to gram positive bacteria is a promising strategy to design novel antibacterial agents. Recently, lipoteichoic acid, a bacterial cell wall glycopolymer, has emerged as a promising and novel target for antimicrobial action. The enzyme, lipoteichoic acid synthase (LtaS) has been recognized as a key enzyme in LTA biosynthesis.

 Materials & Methods: In the present work, we designed triazole-3-thione based compounds and performed in- silico studies to predict and analyse some commonly used computational tools. The study involved assessment of drug likeliness, prediction and analysis of ADMET parameters by pkCSM and swissADME on the synthesized compounds. The molecular docking study was performed using autodock 4.2 targeting lipoteichoic acid synthase (LtaS) on PDB: 2W5S and interaction of the compounds and inhibition constant were studied.

 Result & Discussion: All test compounds passed drug likeliness and majority of the compounds had potential to act as enzyme inhibitor or as ligand for G-protein coupled receptors in bioactivity prediction study. The ADMET analysis suggested the compounds suitable for oral administration due to better permeability and intestinal absorption, high tissue distribution, substrate for CYP3A4, CYP2C19 inhibitor, less mutagenic, low MRTD, less hepatotoxicity and none of the compound had potential for fatal ventricular arrythmia. In Docking study, 11 compounds were found to have better affinity with the active site and were able to make stable complexes based upon binding energy data. The compound K24 having thiophene at 5-position and 3-chloro phenyl at 4-position of triazole-3-thione ring was considered as most active compound based on binding energy, inhibition constant value and H-bond interaction with active residue.