Identification of novel inhibitors targeting Mycobacterium abscessus InhA through virtual screening, docking, and molecular dynamic simulations

Effective treatment options for Mycobacterium abscessus (MAB) pulmonary diseases (PD) are limited due to inadequate drug efficacy, rising drug resistance, and genetic mutations. New compounds are urgently needed to treat MAB-PD. The MAB Enoyl Acyl Carrier Protein (ACP) Reductase InhA (MAB-InhA) plays a crucial role in mycobacterial cell death and mycolic acid (MA) biosynthesis, making it a potential drug target for new lead identification. The purpose of this study was to identify new potential inhibitors of MAB-InhA in MAB-PD by using structure-based virtual screening, docking, molecular mechanics-based generalized born surface area (MM/GBSA), Absorption, Distribution, Metabolism, and Excretion (ADME), and molecular dynamics (MD) simulations. The Enamine antibacterial library containing 32,000 compounds was prepared using phase to create the database. The identified hits were analysed using the phase score, which combines vector alignments, volume score, and root-mean-square deviation (RMSD) site matching. Based on the docking results and obtained scores of the Glide docking tool, we identified Z2378320480 (Z1), Z1188959831 (Z2), Z5292493137 (Z3), Z2437620504 (Z4), Z2440336150 (Z5), and Z3390516726 (Z6) ligand molecules as potential hits. MD simulations (200 ns) were conducted on the best-docked poses of potential hits Z4, Z5, and Z6 to analyse stability and interaction at the MAB-InhA active site. The MD simulation trajectories, including RMSD, root mean square fluctuation (RMSF), ligand-protein interaction, 2D principal component analysis (PCA), and molecular dynamics secondary structure analysis (SSE), were analysed to interpret the stability.