Dihydropyrimidine derivatives as MDM2 inhibitors

Abstract One of the chief pathways to regulate p53 levels is MDM2 protein, which negatively controls p53 by direct inhibition. Many cancers overproduce MDM2 protein to interrupt p53 functions. Therefore, impeding MDM2's binding to p53 can reactivate p53 in tumor cells may suggest an effective approach for tumor therapy. Here, some Monastrol derivatives were designed in silico as MDM2 inhibitors, and their initial cytotoxicity was evaluated in vitro on MFC‐7 and MDA‐MB‐231 cells. A small library of Monastrol derivatives was created, and virtual screening (VS) was performed on them. The first‐ranked compound, which was extracted from VS, and the other six compounds 5a‐5f were selected to carry out the single‐docking and docking with explicit waters. The compound with the best average results was then subjected to molecular dynamic (MD) simulation. Compounds 5a‐5f were chemically synthesized and evaluated in vitro for their initial cytotoxicity on MFC‐7 and MDA‐MB‐231 cells by MTT assay. The best compound was compound 5d with ΔG ave = −10.35 kcal/mol. MD simulation revealed a median potency in comparison with Nutlin‐3a. The MTT assay confirmed the docking and MD experiments. 5d has an IC 50 of 60.09 μM on MCF‐7 cells. We attempted to use Monastrol scaffold as a potent inhibitor of MDM2 rather than an Eg5 inhibitor using in silico modification. The results obtained from the in silico and in vitro evaluations were noteworthy and warranted much more effort in the future.