In silico identification of dual HDAC8 and MMP9 inhibitors by pharmacophore modeling, molecular docking, and molecular dynamics simulation studies for development of antitumour agent

Recent analyses have highlighted the promotion of cancer migration and invasion, mediated through HDAC via MMPs. Since both HDAC8 and MMP9 are involved in the proliferation, migration and invasion of cancer, an attempt has been taken to repurpose DrugBank molecules as dual HDAC8/MMP9 inhibitors by e-pharmacophore mapping, molecular docking and molecular dynamic simulations. Therefore, a comprehensive integrated in silico approach has been adopted. An initial e-pharmacophore model generation based on the co-ligands associated with HDAC8 and MMP9 and subsequent pharmacophore based virtual screening of 12223 drug molecules were performed which eventually yielded 31 hits which corresponded to both the obtained pharmacophoric hypotheses. Then, these hits were docked into HDAC8 and MMP9 crystal structures which resulted in ten hits having better docking scores against both the proteins as compared to that of their respective control drugs. These ten hits were then additionally redocked into other HDAC and MMP isoforms to confirm their isoform selectivity. Out of the ten hits, only DB01834 was found to be dual HDAC8/MMP9 inhibitor having greater affinity to HDAC8 and MMP9 and lower affinity toward other HDACs and MMPs. Finally, molecular dynamics simulation analyses showed that DB01834 had stable interaction with both the HDAC8 and MMP9 protein binding sites. In silico toxicity studies brought to limelight the safety profile of the hit. In silico cytotoxicity prediction studies revealed potent anticancer activity of the hit.