Computational investigation of pyrrolidin derivatives as novel GPX4/MDM2–p53 inhibitors using 2D/3D-QSAR, ADME/toxicity, molecular docking, molecular dynamics simulations, and MM-GBSA free energy

The p53 is a tumor suppressor protein that adjusts cell cycle and growth arrest as well as genes that restore DNA damage and apoptosis. Murine double minute 2 (MDM2) is a main p53 antagonist. We created a novel QSAR model using a series of highly active spiro [pyrrolidin-3,2-oxindoles] that consisted of 29 compounds that were experimentally validated to inhibit the MDM2-p53 interaction. Three optimal models have been developed CoMFA/E + S, CoMSIA/S + H + A, and HQSAR have revealed good statistical results, but the CoMSIA mode only which validates all the external validation tests applied successfully. Based on the CoMSIA/S + H + A model was carefully chosen to design four compounds with values of inhibitory activity greater than the highly active compound in the data set. The newly designed compounds were docked in the target receptor binding site (ID: 4LWU). The newly designed compound Pred 01 showed the highest affinity with a value of − 9.4 kcal/mol, while compound No. 04 which represents the data set and control compound (Nutlin-3) showed binding energies of the order of − 8.8 kcal/mol and − 8.2 kcal/mol, respectively. In addition, ADME/toxicity prediction and the drug-likeness predicted out of Lipinski’s rule and Veber’s rule were estimated; the results obtained demonstrate that the proposed molecules involve good oral bioavailability and an ability to diffuse through different biological barriers. For in-depth study, The Pred01/receptor, No. 04/receptor, and Nutlin-3/receptor complexes were selected via dynamic simulation analyzes with a simulation time of 100 ns and, also, their free binding energy was examined operating the MM-GBSA approach. The molecular docking results obtained accentuate the crucial residues responsible for the ligand/protein interaction, providing insight into the mode of interaction. The MD simulation analysis confirms the conformational stability of the selected complexes during the MD trajectory, and the fluctuations recorded are insignificant. The results of MM-GBSA reveal that the new compound Pred 01 exhibits the lowest free energy, which confirms the result of molecular docking.