Ligand‐Based Pharmacophore Modeling and Virtual Screening of RAD9 Inhibitors

Abstract

Human RAD9 is a key cell‐cycle checkpoint protein that participates in DNA repair, activation of multiple cell cycle phase checkpoints, and apoptosis. Aberrant RAD9 expression has been linked to breast, lung, thyroid, skin, and prostate tumorigenesis. Overexpression of RAD9 interacts with BCL‐2 proteins and blocks the binding sites of BCL‐2 family proteins to interact with chemotherapeutic drugs and leads to drug resistance. Focusing on this interaction, the present study was designed to identify the interaction sites of RAD9 to bind BCL‐2 protein and also to inhibit RAD9‐BCL‐2 interactions by designing novel small molecule inhibitors using pharmacophore modeling and to restore BCL‐2 for interacting with anticancer drugs. The bioactive molecules of natural origin act as excellent leads for new drug development. Thus, in the present study, we used the compounds of natural origin like camptothecin, ascididemin, and Dolastatin and also compared them with synthetic molecule NSC15520. The results revealed that camptothecin can act as an effective inhibitor among all the ligands taken and can be used as an RAD9 inhibitor. The amino acids ARG45 and ALA134 of RAD9 protein are interacting commonly with the drugs and BCL‐2 protein.