Discovery of novel isoform-selective histone deacetylases 5 and 9 inhibitors through combined ligand-based pharmacophore modeling, molecular mocking, and molecular dynamics simulations for cancer treatment

Class IIa histone deacetylases (HDACs) 5 and 9 play crucial roles in several human disorders such as cancer, making them important targets for drug design. Continuous research is pursed to overcome the cytotoxicity side effect that comes with the currently available broad-spectrum HDACs inhibitors. Herein, common features of active HDACs inhibitors in clinical trials and use have been calculated to generate the best pharmacophore hypothesis. Guner-Henry scoring system was used to validate the generated hypotheses. Hypo1 of HDAC5 and Hypo2 of HDAC9 exhibited the most statistically significance hypotheses. Compounds with fit value of 3 and more were examined by QuickVina 2 docking tool to calculate their binding affinity toward all class IIa HDACs. A total of 6 potential selective compounds were subjected to 100 molecular dynamics (MD) simulation to examine their binding modes. The free binding energy calculations were computed according to the MM-PBSA method. Proposed selective compounds displayed good stability with their targets and thus they may offer potent leads for the designing of HDAC5 and HDAC9 isoform selective inhibitors. [Display omitted] •Common pharmacophoric features were generated based on active class IIa HDACs known inhibitors.•Best hypotheses were validated and selected according to Guner and Henry scoring system.•ZINC15 database was screened against Hypo1 and Hypo2 for discovering of novel inhibitors.•4 potent compounds displayed isoform-selective inhibitors for HDAC5 and HDAC9.