Cross-docking study on InhA inhibitors: a combination of Autodock Vina and PM6-DH2 simulations to retrieve bio-active conformations.

InhA, the NADH-dependent enoyl-acyl carrier protein reductase from Mycobacterium tuberculosis (Mtb) is the proposed main target of the first-line antituberculosis drug isoniazid (INH). INH activity is dependent on activation by the catalase peroxidase KatG, a Mtb enzyme whose mutations are linked to clinical resistance to INH. Other inhibitors of InhA that do not require any preliminary activation are known. The design of such direct potent inhibitors represents a promising approach to circumvent this resistance mechanism. An ensemble-docking process with four known InhA X-ray crystal structures and employing the Autodock Vina software was performed. Five InhA inhibitors whose bioactive conformations are known were sequentially docked in the substrate cavity of each protein. The efficiency of the docking was assessed and validated by comparing the calculated conformations to the crystallographic structures. For a same inhibitor, the docking results differed from one InhA conformation to another; however, docking poses that matched correctly or were very close to the expected bioactive conformations could be identified. The expected conformations were not systematically well ranked by the Autodock Vina scoring function. A post-docking optimization was carried out on all the docked conformations with the AMMP force field implemented on the VEGAZZ software, followed by a single point calculation of the interaction energy, using the MOPAC PM6-DH2 semi-empirical quantum chemistry method. The conformations were subsequently submitted to a PM6-DH2 optimization in partially flexible cavities. The resulting interaction energies combined with the multiple receptor conformations approach allowed us to retrieve the bioactive conformation of each ligand.