N-myristoyl transferase inhibitors from natural sources: A molecular docking exploration

The control of fungal pathogens remains as a current priority. Thus, the discovery of antifungal compounds from natural sources might be a good alternative. Several studies have been focused on the evaluation of the antimicrobial activity of naturally-occurring compounds, suggesting interesting leads to further studies. However, the lack of molecular studies becomes an obstacle in the course for developing natural products-based drug design. An important enzyme target for fungicides design is the N-myristoyl transferase (NMT), which catalyzes the transfer of the 14-carbon saturated fatty acid myristate from myristoyl-CoA to the N-terminal glycine residue. NMT is involving in vital diverse biological processes. Therefore, as part of our research on antifungal compounds, a set of bioactive compounds – isolated from several sources and reported with antimicrobial activity – were investigated in order to explore the binding affinity with NMT through molecular docking. A non-peptidic inhibitor having a benzofuran core was used as control. Autodock/Vina was employed to dock the most stable conformers of 33 bioactive compounds within the active site of Candida albicans NMT (CaNMT). Stability of enzyme complexes was analyzed through Vina scores and selected active site residues interactions. Good Vina scores were obtained for enzyme-ligand complexes interactions at different levels into the -5.1 – -8.7 kcal/mol range. Most stable conformers of isopiscerythrone and berberine were found to exhibit the best Vina-scores. Residue-ligand interaction profile was correlated with Vina scores, exhibiting important structure-interaction relationships useful in further studies. Tyr225 and Phe240 residues were found to be crucial polar contacts for the docked complexes. The present work is a product derived by the Project CIAS-1331 financed by Vicerrectoría de Investigaciones at UMNG – Validity 2013.