From pan-genome to protein dynamics: A computational hierarchical quest to identify drug target in multi-drug resistant Burkholderia cepacia

Abstract Burkholderia cepacia has emerged as a significant infectious agent that exhibits resistance to major classes of antibiotics and novel therapeutic approaches are necessitated to address this pathogen. Glutamate racemase (GR) has been revealed as highly potent and safe drug target by pan-genome analysis. It plays role in the interconversion of L-Glutamate to D-Glutamate and remains an essential element of the peptidoglycan layer. Docking guided virtual screening is carried out predicting a lead molecule: “(R)-1-((5-((1R, 6R)-6-carboxycyclohexa-2, 4-dien-1-yl) thiazol-2-yl) methyl)-3-oxopiperazin-1-ium” possess the best fitting conformation to the target. It is found that heterocyclic ring of the molecule has a key role in the binding affinity of the target protein. During simulation, the inhibitor interacts with the allosteric site, allowing the heterocyclic ring to be positioned at the adjacent substrate binding site. Local secondary structures interconversion is seen regularly in both chains of the protein. The radial distribution function investigated Leu24 as closely placed at 1.9 A with an average g (r) value 0.8 to the binding site residues during the course of simulation. The density of the interactive space shows that Leu24 and Asn85 are the most active residues with average binding energies of −2.65 kcal/mol and −2.36 kcal/mol, respectively and affirms strong hydrogen bonding. Total binding energies in both MMPB/GBSA results in −21.13 kcal/mol and −36.41 kcal/mol are contributing heavily towards the stability. Interestingly, the Waterswap approach exhibits accurate binding energies of −20.16 kcal/mol. This chemical entity is adjacent to medicinally active molecules and in line with the previous research which showed thiazol subunits and its derivatives bearing many biological functions. In order to validate compound antibacterial activity, it is necessary to investigate the biological potency of the compound using biological assays and could be promising for experimentalists in the future to address this multi-drug resistant pathogen.