Computational study on natural molecules targeting β-ketoacyl reductase domain of fatty acid synthase for the identification of selective inhibitors

Fatty acid synthase (FASN) enzyme is a lipid metabolism protein that provides the essential nutrients to cancer cells through de novo lipogenesis. Also, it plays a key role in other disease conditions, including obesity and inflammation. Hence, targeting the β-ketoacyl reductase (KR) domain of FASN protein, an in-silico study was performed on some selective bioactive natural molecules following a repurposing strategy to identify FASN inhibitors. A molecular docking study followed by Absorption, Distribution, Metabolism and Excretion (ADME) predictions, binding free energy calculations, and molecular dynamics (MD) simulations were performed against FASN protein (PDB ID:6NNA) using Schrodinger Drug Discovery Software. Compounds rutin, trans-chlorogenic acid, norbergenin, myricetin, quercetin, physalolactone, quercetin-3-O-galactoside, kaempferol, asperulosidic acid, luteolin, curcumin, 12-deoxywithastramonolide, pedunculoside, hernandifoline, and withafastuosin E were identified as hits, presenting better docking scores (-16.2, -14.1, -12.3, -12.1, -12.0, -11.3, -10.3, -9.8, -9.3, -9.2, -9.1, -8.5, -8.4, -8.3, -7.9, respectively) and hydrogen bond interactions with Ser 2021 and Tyr 2034 amino acids of the KR domain of FASN. The MD simulations study of top five hits in complex with protein 6NNA uncovered the significant interactions leading to the stabilization of ligand with Root Mean Square Deviation (RMSD) below 5.00 Å and the stability was further validated by evaluating the root mean square fluctuation, solvent accessible surface area, and radius of gyration graphs. Also, the FASN inhibition effect of top four hits (50 µM) was >50% when corroborated using High Performance Liquid Chromatography HPLC-based estimation of palmitic acid in MCF-7 cells. Thus rutin, trans-chlorogenic acid, norbergenin, and myricetin are proposed as prospective FASN inhibitory leads. Overall, the results provided useful modifications in pharmacophoric features that could improve the inhibitory effect.Communicated by Ramaswamy H. Sarma.