DESIGN AND ANTICANCER ACTIVITY PREDICTION OF DIHYROPYRIMIDINONE BASED NOVEL INHIBITORS OF P53-MDM2 INTERACTION

  • Surendra Kumar Nayak Department of Pharmaceutical Chemistry, School of Pharmaceutical Sciences, Lovely Professional University, Jalandhar-Delhi, G. T. Road (NH-1), Phagwara, Punjab -144 411, India.
  • Gopal Lal Khatik Department of Pharmaceutical Chemistry, School of Pharmaceutical Sciences, Lovely Professional University, Jalandhar-Delhi, G. T. Road (NH-1), Phagwara, Punjab -144 411, India.
  • Rakesh Narang Department of Pharmaceutical Chemistry, School of Pharmaceutical Sciences, Lovely Professional University, Jalandhar-Delhi, G. T. Road (NH-1), Phagwara, Punjab -144 411, India.
  • Harish Kumar Chopra Department of Chemistry, Sant Longowal Institute of Engineering and Technology (Deemed University), Longowal, Sangrur - 148 106, India.

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 IC50, 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.

Keywords: Anticancer, Dihydropyrimidinone, MDM2, p53, Toxicity.

Author Biography

Surendra Kumar Nayak, Department of Pharmaceutical Chemistry, School of Pharmaceutical Sciences, Lovely Professional University, Jalandhar-Delhi, G. T. Road (NH-1), Phagwara, Punjab -144 411, India.
School of Pharmaceutical Sciences, Asst. Prof

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Nayak, S. K., G. L. Khatik, R. Narang, and H. K. Chopra. “DESIGN AND ANTICANCER ACTIVITY PREDICTION OF DIHYROPYRIMIDINONE BASED NOVEL INHIBITORS OF P53-MDM2 INTERACTION”. Asian Journal of Pharmaceutical and Clinical Research, Vol. 10, no. 16, Sept. 2017, pp. 110-6, doi:10.22159/ajpcr.2017.v10s4.21346.
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