Molecular docking/dynamic simulations, MEP, ADME-TOX-based analysis of xanthone derivatives as CHK1 inhibitors

CHK1 is a promising molecular target that gained immense attention recently for the development of cancer therapeutics. In this study, a simulation-based investigation was conducted to examine the CHK1 inhibitory activity of cytotoxic xanthone derivatives using a hierarchical workflow for molecular docking, MD simulation, ADME-TOX prediction, and MEP analysis. A molecular docking study was conducted for the forty-three xanthone derivatives along with standard prexasertib into the selected CHK1 protein structures 7AKM and 7AKO. Eight top hits were identified based on their free energy scores, namely L43, L42, L41, L40, L36, L33, L31, and L30, which showed better binding affinity (from − 8.22 to − 8.08 kcal/mol) (from − 8.14 to − 7.9 kcal/mol) toward 7AKM and 7AKO, respectively than the reference prexasertib which emphasizes the validity of our strategy. Furthermore, MD studies support molecular docking results and validate the stability of studied complexes in physiological conditions. These findings confirm that the selected eight xanthones are verifiable CHK1 inhibitors implying a good correlation between in silico and in vitro studies. Moreover, in silico ADME-TOX studies are used to predict the pharmacokinetic, pharmacodynamic, and toxicological properties of the studied eight hits and the standard prexasertib. Indeed, L36 showed the best ADME-TOX profile as it was the only hit without hepatotoxicity among the studied compounds. Besides, it displayed superior binding affinity and satisfied Lipinski, Pfizer, and golden triangle rules indicating a potent drug candidate. The quantitative analysis of electrostatic potential was performed for L36 to identify the reactive sites and possible non-covalent interactions.