Weak spots inhibition in the <i>Mycobacterium tuberculosis</i> antigen 85C target for antitubercular drug design through selective irreversible covalent inhibitor-SER124

Abstract

<i>Mycobacterium tuberculosis</i> (<i>Mtb</i>) encoded secreted antigen 85 enzymes (Ag85A/Ag85B/Ag85C) play that critical roles in the virulence, survival and drug-resistant TB of the pathogen. Ag85 proteins are potential antitubercular drug targets because they are essential in the catalytic synthesis of trehalose moieties and mycolic acid attachment to the <i>Mtb</i> cell wall. Recently, experimental protocols led to the discovery of a selective covalent Ag85 inhibitor, β-isomer monocyclic enolphosphorus Cycliphostin (CyC_8β) compound, which targets the Ag85 serine 124 to exhibit a promising therapeutic activity. For the first time, our study unravelled the structural features among <i>Mtb</i> Ag85C homologs and motions and dynamics of Ag85C when the CyC_8β bound covalently and in open model conformations to the protein using bioinformatics tools and integrated Molecular dynamics simulations. Comparative Ag85C sequence analysis revealed conserved regions; 70% active site, 90% Adeniyi loop L1 and 50% loop L2, which acts as a switch between open and closed conformations. The average C-α atoms RMSD (2.05 Å) and RMSF (0.9 Å) revealed instability and high induced flexibility in the CyC_8β covalent-bound compared to the apo and open model systems, which displayed more stability and lower fluctuations. DSSP showed structural transitions of α-helices to bend and loops to 3₁₀-helices in the bound systems. SASA of CyC_8β covalent bound showed active site hydrophobic residues exposure to huge solvent. Therefore, these findings present the potential opportunity hotspots in Ag85C protein that would aid the structure-based design of novel chemical entities capable of resulting in potent antitubercular drugs.Communicated by Ramaswamy H. Sarma.