Discovery of Mycobacterium tuberculosis InhA Inhibitors by Binding Sites Comparison and Ligands Prediction

Abstract

Drug discovery is usually focused on a single protein target; in this process, existing compounds that bind to related proteins are often ignored. We describe ProBiS plugin, extension of our earlier ProBiS-ligands approach, which for a given protein structure allows prediction of its binding sites and, for each binding site, the ligands from similar binding sites in the Protein Data Bank. We developed a new database of precalculated binding site comparisons of about 290000 proteins to allow fast prediction of binding sites in existing proteins. The plugin enables advanced viewing of predicted binding sites, ligands’ poses, and their interactions in three-dimensional graphics. Using the InhA query protein, an enoyl reductase enzyme in the Mycobacterium tuberculosis fatty acid biosynthesis pathway, we predicted its possible ligands and assessed their inhibitory activity experimentally. This resulted in three previously unrecognized inhibitors with novel scaffolds, demonstrating the plugin’s utility in the early drug discovery process.

Inverse Molecular Docking as a Novel Approach to Study Anticarcinogenic and Anti-Neuroinflammatory Effects of Curcumin

“…Inverse molecular docking was performed with the fragment-based CANDOCK program [37], which was used to screen curcumin against all available human protein structures obtained from the Protein Data Bank (PDB) [38]. As blind docking was unfeasible due to the size of the PDB, we identified small molecule binding sites on the proteins and prepared them for inverse docking according to the procedure described in [39]. A binding site was defined as the space occupied by the union of one to several ligands that bind to similar binding sites and for which a co-crystal structure exists in the PDB.…”

“…The docking search space was therefore focused on binding sites, which reduced the time complexity of the inverse docking. A previous version of this database was successfully used for discovery of small-molecule inhibitors of inhibin α (InhA) enzyme in Mycobacterium tuberculosis and this resulted in the identification of three previously unrecognized inhibitors with novel scaffolds [39].…”

Overcoming cancer therapeutic bottleneck by drug repurposing

“…455,456 Following up on these findings, Salentin et al used the Protein Data Bank, which contains structural data for more than one thousand different drug targets, to explore any drug-target pairs, which have similar interactions with BVDU and thymidine kinase. 457,458 The antimalarial drug amodiaquine was found to inhibit HSP27 chaperone function and reverse tumor drug resistance in multiple myeloma cell lines. Binding site comparisons are also a popular approach to predict similar pharmacological drugs.…”

Identification and validation of the mode of action of the chalcone anti-mycobacterial compounds

“…Recently Joshi et al (2017) have used target to drug approach and shown that compounds such as pyrrolyl benzohydrazide derivatives inhibit InhA directly. Similarly Stular et al (2016) using molecular docking found three novel compounds that bind InhA. Biological testing confirmed that these compounds inhibit InhA.…”