Targeting p53-MDM2 interactions to identify small molecule inhibitors for cancer therapy: beyond “Failure to rescue”

Abstract

At present, disrupting p53-MDM2 interactions through small molecule ligands is a promising approach to safe treatment and management of human cancer. Tumor cells unlike the normal cells, are rapidly evolving affecting the efficacy of many approved anti-cancer agents due to drug resistance. Therefore, identifying a potential anticancer compound is crucial. Pharmacophore based virtual screening, followed by molecular docking, ADMET evaluation, and molecular dynamics studies against MDM2 protein was investigated to identify potential ligands that may act as inhibitors. The model (AHRR_1) with survival score (4.176) was selected among the top ranked generated Pharmacophore hypothesis. Validation of the model hypothesis by an external dataset of actives and inactive compounds produced significant validation attributes including; AUC = 0.85, BEDROC = 0.56 at α = 20.0, RIE = 8.18, AUAC = 0.88, and EF of 6.2 at the top 2% of the dataset. The model was use for screening the ZINC database, and the top 1375 hits satisfying the model hypothesis were subjected to molecular docking studies to understand the molecular and structural basis of selectivity of compounds for MDM2 protein. A sub-set of 25 compounds with binding energy lower than the reference inhibitors were evaluated for pharmacokinetic properties. Four compounds (ZINC02639178, ZINC06752762, ZINC38933175, and ZINC77969611) showed the most desired pharmacokinetic profile. Lastly, investigation of the dynamic behaviour of leads-protein complexes through MD simulation showed similar RMSD, RMSF, and H-bond occupancy profile compared to a reference inhibitor, suggesting stability throughout the simulation time. However, ZINC02639178 was found to satisfy the molecular enumeration the most compared to the other three leads. It may emerge as potential treatment option after extensive experimental studies.

Communicated by Ramaswamy H. Sarma

Graphical Abstract

Keywords:

• Cancer therapy
• small molecule inhibitors
• molecular docking
• molecular dynamics simulation
• pharmacophore-based virtual screening
• p53-MDM2 interaction
• regeneration

Acknowledgements

The authors ‘are thankful to the developer of all the computational tools used for the completion of this study. The authors gratefully appreciate Dr. Suyant Pant, National Institute of Pharmaceutical Education and Research Kolkata-700054, west Bengal India, for his contributions to the success and for his encouragement to carry out this work.

Disclosure statement

We declare no known competing financial interests or proposal relationships that could have appeared to influence this current study.

Ethical consent

Not applicable.

Authors’ contributions

The study in this manuscript was collaboratively executed by all aforementioned authors. POC conceptualize the idea and design the experiment described in this study. POC, HIU, and OI were involved in the investigation process of this study by conducting the experiment, analysing and evaluating the results of the molecular docking and molecular dynamics simulation. CBO and FOI were involved in the validation and visualization of the molecular interactions of the reported complexes. OJO, MOE and JOE drafted the manuscript and were involved in the methodology. FJA and OMO edited the manuscript and analysed the results of the druglikeness and pharmacokinetic properties of the selected lead compounds. The overall study was carried out under the supervision of OI and HIU. All the authors read and approved the manuscript.

Additional information

Funding

Not applicable.