Identification of natural product inhibitors of de novo lipogenesis enzymes as an anti-cancer strategy: An in silico approach

Abstract

Dysregulation of the metabolic pathways is fundamental to cancer formation. The differential expression and activation of de novo fatty acid synthase (FASN) and lipogenesis enzymes ATP citrate lyase (ACLY) have been observed in various cancer types making them a promising metabolic target in cancer therapy. Natural products (NP) are a major contributor to the development of novel non-toxic anti-tumour drugs with greater efficiency. An attempt has been made in this study to identify potent orally active ACLY and FASN inhibitors from Universal Natural Product Database (UNPD) through virtual screening (VS). The VS resulted in the discovery of two hit compounds UNPD 80894 and UNPD 100156 as inhibitors of ACLY and FASN respectively. Molecular docking revealed that UNPD 80894 and UNPD 100156 bind at the substrate binding site of ACLY and the entry channel of FASN with a docking score of -8.0 kcal/mol and -5.0 kcal/mol, respectively. Identified hit compounds also obeyed the Rule of Three (RO3) thus making them possible candidates for future fragment-based drug design studies. In silico absorption, distribution, metabolism, excretion and toxicity (ADMET) analysis of the hits predicted desirable pharmacokinetic profiles with no aberrant toxicity. The anti-cancer potentialities of the hits were also analysed using the prediction of activity spectra for substances (PASS) prediction tool which predicted the potential of UNPD 80894 as an inhibitor of ubiquinol-cytochrome-c reductase and UNPD 100156 as a lipoprotein lipase inhibitor and probable application in preneoplastic conditions treatment. These two natural compounds are proposed as potential candidates for the development of a novel ACLY and FASN inhibitors in this study.