Identification of anti-mycobacterial agents against mmpL3: Virtual screening, ADMET analysis and MD simulations

Abstract

• Virtual screening of 175,851 ligands from Asinex BioDesign library for anti-TB agents. • Molecular docking via HTVS, SP, and XP modes of variable precision and accuracy. • Study of drug-likeness using ADMET and Lipinski filters. • Time-dependent stability of the identified hits at active site using MD simulations. Tuberculosis has been the communicable disease being one of the top 10 causes of deaths worldwide and the leading cause of deaths from a single infectious agent (ranking above HIV/AIDS). Mycobacterial mmpL3 target plays significant role in synthesis of essential components of the mycobacterial outer membrane including iron uptake, energy production, membrane potential, and antibiotic susceptibility. The worsening situation of the TB treatment has urged the necessity of search of new anti-tubercular agents through computational chemistry driven in silico approach. In search of mmpL3 inhibitors (PDB ID: 6AJG ), molecular modeling of 175,851 ligands from 2020.1 Asinex BioDesign library through E-pharmacophore based screening followed by virtual screening using three different modes of precision (HTVS, SP and XP), ADMET analysis, Lipinski filters and MD simulations. These studies have provided an important start-point in the field of anti-mycobacterial agents through molecular modeling in search of mmpL3 inhibitors. For the first time, systematic virtual screening of 175,851 ligands from 2020 to 01 Asinex BioDesign library against mmpL3 in search of anti-TB agents has been executed using three different level of precision modes (HTVS, SP, and XP) followed by profiling of ADMET assay and evaluation of drug-likeness in search of potent anti-TB agents. The stability of the identified three hits at active site of co-crystalized SQ109, was evaluated using MD simulations.