Molecular modeling and molecular dynamics simulation studies on pyrrolopyrimidine-based α-helix mimetic as dual...

Inhibition of the interactions between the tumor suppressor protein p53 and its negative regulators, the MDM2 and MDMX oncogenic proteins, is increasingly gaining interest in cancer therapy and drug design. In this study, we carry out molecular docking, molecular dynamics (MD) simulations, and molecular mechanics Poisson-Boltzmann and generalized Born/surface area (MM-PB/GBSA) binding free energy calculations on an active compound 3a and an inactive compound NC-1, which share a common pyrrolopyrimidine-based scaffold. MD simulations and MM-PB/GBSA calculations show that the compound NC-1 may not bind to MDM2 and MDMX, in agreement with the experimental results. Detailed MM-PB/GBSA calculations on the MDM2-3a and MDMX-3a complexes unravel that the binding free energies are similar for the two complexes. Furthermore, the van der Waals energy is the largest component of the binding free energy for both complexes, which indicates that the interactions between the compound 3a and MDM2 and MDMX are dominated by shape complementarity. In addition, the analysis of individual residue contribution and protein-ligand binding mode show that the three functional groups on R₁, R₂, and R₃ of the compound 3a can mimic the spatial orientation of the side chains of Phe19, Trp23, and Leu26 of p53, respectively. The obtained computational results suggest that the compound 3a can act as a dual inhibitor of MDM2-p53 and MDMX-p53 interactions, consistent with the experimental results.