Design and Anticancer Activity Prediction of Dihyropyrimidinone Based Novel Inhibitors of P53-Mdm2 Interaction

Abstract

Objective: P53 protein is well known for its role in cell cycle regulation and induction of apoptosis. This protein is degraded by MDM2 mediated proteolysis. Inhibition of interaction between p53 and MDM2 has been recognized as a most potential and selective target for development of novel anticancer agents. Recently, several molecules entered in the clinical trial study for the treatment of various types of cancers are based on inhibition of interaction between p53-MDM2. Therefore, in this study, a novel dihydropyridine based molecules were designed as p53-MDM2 inhibitor, and their anticancer activity (including reference) was determined in comparison with most active anticancer agent and inactive anticancer agents in National Cancer Institute database using "Cancer IN" server. Methods:In this work, a novel dihydropyrimidinone based lead (L11) on the basis of molecular docking study, predicted IC 50 , anticancer activity, and toxicity profile were designed. Lead L11 was obtained after sequential isosteric replacement of functional groups for optimization in compound L0. Results:The docking scores of L3-L11 found to be in range of 21-25 close to docking score 25 of SAR405838 and better than nutlin-3a. MDM2 binding affinity values (37-78 Kcal/mol) of all ligands were also found to better than that of nutlin-3a (37 Kcal/mol). Surprisingly, MDM2 binding affinity of L11 (78 Kcal/mol) found to be equal to that of SAR405838 and 2-fold greater than nutlin-3a.Conclusion: These data indicating that L11 as a potential lead from dihydropyrimidinones for inhibition of p53-MDM2 interaction.

Dihydropyrimidinones as potent anticancer agents: Insight into the structure–activity relationship

“…MDM2, inhibiting the likeliness estimated (37-78 kcal/mol) of all ligands, was also found to be better than that of nutlin-3a (37 kcal/mol). MDM2 has a better restricting inhibiting likeliness for compound 44 (78 kcal/mol), which is equivalent to that of SAR405838 and two times more potent than nutlin-3a as it imitates the three pivotal build-ups of p53 restricting cavity on MDM2 (Phe19, Trp23, and Leu26), making it a potential lead DHPM in p53-MDM2 connection [65] (Figure 25). had the best in vitro action against the breast cancer and lung cancer cell line.…”

Review of Design Approaches and Clinical Progress of Mdm2 Inhibitors

“…Target-based drug design MDM2 protein consists of a deep hydrophobic pocket in its structure. And this hydrophobic pocket has been packed/filled by the three side chains of the p53 protein (during the interaction) 7 .…”