Annonaceous acetogenins: A computational study into their antitumor activity in multidrug resistant enzymes

Abstract

Abstract Natural products that could reverse tumor drug resistance are promising and highly appreciated; especially, if they are part of combination therapy with conventional anti-cancer drugs. Acetogenins, the long chain polyketide derived fatty acids, from Annona squamosa and muricata were screened in the last 20 years and promising compounds were selected to investigate their activity by computational studies inside the binding pockets of four major MDR enzymes (EGFR, MCL-1, BCL-2, and NQO1). Using virtual screening and molecular docking, compounds were ranked according to their fitting scores and squamostanin A, annupupuricin, Squamocin IV were the best fitting molecules with favorable non covalent interactions with key amino acids compared to native ligands and standards. Subsequently, these compounds in their prepared enzyme complexes were subjected to molecular dynamics stability study to investigate the complex characteristics. The key interactions were confirmed in the molecular dynamic study, which manifested no noticeable unfolding of the binding complexes. The physicochemical and drug likeness properties of all the compounds were evaluated through the QikProp module indicating their suitable ADMET properties within the recommended ranges.