Virtual screening-based identification of novel fatty acid synthase inhibitor and evaluation of its antiproliferative activity in breast cancer cells

Cancer cells activate de novo lipogenesis by overexpressing the lipogenic enzymes ACLY, ACC and FASN to support rapid cell division. FASN, previously known as oncogenic antigen-519 (OA-519) catalyzes seven sequential reactions to synthesize palmitic acid (C16) from substrates acetyl CoA, and malonyl CoA. The dependence of cancer cells on FASN-derived lipids and the differential expression of FASN in cancer cells compared to their normal counterparts make it an attractive metabolic drug target in cancer therapy. In the present study, an attempt has been made to identify potent FASN inhibitors from Asinex-Synergy compound database using structure-based virtual screening. The serial docking protocols of increasing precisions identified LEG-17649942, with glide score −10.34 kcal/mol as a promising compound which can directly interact with active site residues H293 and H331. LEG-17649942 possesses drug-like pharmacokinetic properties as predicted by Qikprop. LEG-17649942 exhibited cytotoxicity in breast cancer cell lines SK-BR-3, MCF-7 and MDA-MB-231 with maximum activity against MDA-MB-231 cells with IC50 of 50 μM. The study put forward LEG-17649942 as a novel drug-lead compound against triple negative breast cancer with an exquisite binding pattern to FASN-KS domain. [Display omitted] •Structure-based virtual screening identified LEG-17649942 as a promising FASN inhibitor.•LEG-17649942 possesses drug-like ADME properties as predicted by Qikprop.•LEG-17649942 induces cytotoxicity in MDA-MB-231 breast cancer cells with an IC50 of 50 µM.