Targeting allosteric sites of human aromatase: a comprehensive <i>in-silico</i> and <i>in-vitro</i> workflow to find potential plant-based anti-breast cancer therapeutics
Hani A. Alhadrami, Ahmed M. Sayed, Sami Melebari, Asim Khogeer, Wesam H. Abdulaal, Mohamed B. Al‐Fageeh, Mohammad Algahtani, Mostafa E. Rateb
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.