Characterization of Alternaria alternata alternariol monomethyl ether with a potential antiproliferative activity by topoisomerases inhibition; molecular docking and dynamic simulations

Abstract The drug resistance is one of the challenges in cancer chemotherapy, due to the development of different drug-efflux pumps that expels the drug out of the cells, thus, searching for new compounds with multiple targets in tumor cells, could be an affordable chemotherapy. Alternariol monomethyl ether (AME) was preliminary recognized as a cytotoxic compound, however, its availability and equivocal activity are the hurdles for further applications. Alternaria alternata EFBL-025, PV342518.1 , endophyte of Catharanthus roseus, exhibited the highest AME productivity (550 μg/l). Chemically, the structure of putative compound of A. alternata was committed from the TLC, HPLC and LC-MS/MS, with molecular mass 274.2 m/z, and typical fragmentation pattern of authentic AME. The purified AME of A. alternata exhibited a substantial activity against the MCF-7 (IC 50 2.5 μM), HepG-2 (IC 50 3.5 μM), Caco2 (IC 50 3.9 μM), compared to OEC (IC 50 13.5 μM), i.e with selectivity indices 5.4, 3.9 and 3.5, respectively. The AME has a highest inhibitory activity of Topoisomerase II (IC 50 10.2 nM), than Topoisomerase I (IC 50 16.7 nM), with a noticeable ability to arrest the division of MCF-7 cells at the G2/M and S phases by 1.5 and 2 folds, respectively, compared to the control. The AME of A. alternata significantly induces the total apoptosis, early apoptosis and necrosis of MCF-7 by 20, 22 and 2.9 folds. The docking analysis showed that AME had a favorable binding affinity for topoisomerases I/II with binding scores -7.72 and -6.06 kcal/mol, normalized to camptothecin and etoposide that have binding scores -9.44 and -6.82 kcal/mol, respectively. The molecular dynamics simulations explored the reliable stability of protein-AME complexes.