Mukesh Nandave

Fatty acid synthase (FASN) is a key enzyme involved in neoplastic lipogenesis and accumulating evidence suggests that overexpression of FASN is common in many cancers. To date, not many compounds are known to inhibit FASN. Thus, our aim was to explore more lead compounds which are able to inhibit FASN. High affinity compounds for FASN were searched among a database of chemical structures comprising 9,127 approved drugs, chemical isolates from traditional medicinal herbs, and regulated chemicals, termed the SWEETLEAD. The screening protocol consisted of a high-throughput pharmacophore screening followed by an extensive docking and scoring study. Three different pharmacophore models and a merged pharmacophore model were generated using three different inactive crystal structures of FASN. Pharmacophore-based screening yielded overall 1,661 hits. Afterwards, all these hit compounds were docked to the inactive form of FASN using docking and scoring protocols. The best pose was further evaluated based on the existence of key residues for antagonist binding in its vicinity which retrieved 38 hits. After final evaluations based on S-score, 12 hits were revealed. Although the experimental validation of these compounds are lacking, computational methods predicts them as strong binders. Further experimental validation of these compounds will confirm this in silico study and their potential role of these hits in treatment of cancer with high FASN expression.