Targeting allosteric sites of human aromatase: a comprehensive in-silico and in-vitro workflow to find potential plant-based anti-breast cancer therapeutics. (1st January 2021)

• Record Type: Journal Article
• Authors: Alhadrami, Hani A.; Sayed, Ahmed M.; Melebari, Sami A.; Khogeer, Asem A.; Abdulaal, Wesam H.; Al-Fageeh, Mohamed B.; Algahtani, Mohammad; Rateb, Mostafa E.
• Is Part Of: Journal of enzyme inhibition and medicinal chemistry. Volume 36:Number 1(2021)
• Page Start: 1333
• Page End: 1344
• Publication Date: 2021-01-01
• Subjects: Aromatase -- anti-breast cancer -- allosteric inhibition -- natural products -- in silico; Enzyme inhibitors -- Periodicals; Enzyme Inhibitors -- periodicals; Biochemistry -- periodicals; 572.7
• DOI: 10.1080/14756366.2021.1937145
• Languages: English
• ISSNs: 1475-6366

Abstract

Abstract: Recent findings suggested several allosteric pockets on human aromatase that could be utilised for the development of new modulators able to inhibit this enzyme in a new mechanism. Herein, we applied an integrated in-silico -based approach supported by in-vitro enzyme-based and cell-based validation assays to select the best leads able to target these allosteric binding sites from a small library of plant-derived natural products. Chrysin, apigenin, and resveratrol were found to be the best inhibitors targeting the enzyme's substrate access channel and were able to produce a competitive inhibition with IC50 values ranged from 1.7 to 15.8 µM. Moreover, they showed a more potent antiproliferative effect against ER+ (MCF-7) than ER- one (MDA-MB-231) cell lines. On the other hand, both pomiferin and berberine were the best hits for the enzyme's haem-proximal cavity producing a non-competitive inhibition (IC50 15.1 and 21.4 µM, respectively) and showed selective antiproliferative activity towards MCF-7 cell lines.