Group-based QSAR and molecular dynamics mechanistic analysis revealing the mode of action of novel piperidinone derived protein–protein inhibitors of p53-MDM2

• A novel group-based QSAR model was developed for a series of piperidinone derived compounds as p53-MDM2 protein–protein interaction abrogators.
• Based on the QSAR model, a combinatorial library of compounds was generated for improved activities.
• Top two compounds with high inhibitory activity were also found possessing high binding affinity towards MDM2.
• Long molecular dynamics simulations of the ligand-bound complexes revealed stable binding.
• The study potentiates these compounds as prospective novel leads against cancer and provides their detailed binding mode of actions.

Tumour suppressor p53 is known to play a central role in prevention of tumour development, DNA repair, senescence and apoptosis which is in normal cells maintained by negative feedback regulator MDM2 (Murine Double Minute 2). In case of dysfunctioning of this regulatory loop, tumour development starts thus resulting in cancerous condition. Inhibition of p53-MDM2 binding would result in activation of the tumour suppressor. In this study, a novel robust fragment-based QSAR model has been developed for piperidinone derived compounds experimentally known to inhibit p53-MDM2 interaction. The QSAR model developed showed satisfactory statistical parameters for the experimentally reported dataset (r2 = 0.9415, q2 = 0.8958, pred_r2 = 0.8894 and F-test = 112.7314), thus judging the robustness of the model. Low standard error values (r2_se = 0.3003, q2_se = 0.4009 and pred_r2_se = 0.3315) confirmed the accuracy of the developed model. The regression equation obtained constituted three descriptors (R2-DeltaEpsilonA, R1-RotatableBondCount and R2-SssOCount), two of which had positive contribution while third showed negative correlation. Based on the developed QSAR model, a combinatorial library was generated and activities of the compounds were predicted. These compounds were docked with MDM2 and two top scoring compounds with binding affinities of −10.13 and −9.80 kcal/mol were selected. The binding modes of actions of these complexes were analyzed using molecular dynamics simulations. Analysis of the developed fragment-based QSAR model revealed that addition of unsaturated electronegative groups at R2 site and groups with more rotatable bonds at R1 improved the inhibitory activity of these potent lead compounds. The detailed analysis carried out in this study provides a considerable basis for the design and development of novel piperidinone-based lead molecules against cancer and also provides mechanistic insights into their mode of actions.

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