Molecular docking, in-vitro anticancer evaluation and ADME profiling of 7-Oxo Midostaurin

Abstract

Midostaurin drug is used for treatment of acute myeloid leukaemia, myelodysplastic syndrome, and advanced systemic mastocytosis. Midostaurin under-went oxidation reaction and formed the degradation product (7-Oxo-midostaurin or MDS DP1). Therefore, an anti-cancer efficacy was investigated for MDS DP1 using the molecular docking, in-vitro proliferation, and ADME studies. Molecular docking simulations showed that the MDS DP1 had effectively docked with the active site of the crystal structure of BCL-2 with Venetoclax (PDB ID: 6O0K), resulting in enhanced inhibitory activity (docking score, -9.81 kcal/mol). In-vitro cytotoxicity tests using the CVS assay proved that MDS DP1 had the most promising anti-cancer behavior. The IC50 results of MDS DP1 obtained from CVS assay were 12.71, 13.04, and 17.50 µM against the human cancer cell lines of MDA-MB-231, A549 and HCT-116, which were found to be almost similar to that of the referenced anti-cancer drugs of Midostaurin (IC50: 14.81, 26.34, and 20.45 µM) and Doxorubicin (IC50: 15.06, 15.31, and 18.16 µM). Further, Lipinski's Rule of Five with QSAR models was utilized to predict the physicochemical and pharmacokinetic properties (ADME profiling) of MDS DP1.