Prediction of dual agents as an activator of mutant p53 and inhibitor of Hsp90 by docking, molecular dynamic simulation and virtual screening

•The new ligand was confirmed as a dual agent by molecular docking study and molecular dynamic simulations.•Results were evaluated by molecular dynamic simulations on an Hsp90 pyrazole inhibitor and a p53 pyrazole activator that those activities had been confirmed through experimental research.•A virtual screening was performed on ZINC database and a set of new dual agents has been proposed.•These compounds show that substitution of pyrrole ring or any other group at position 3 of pyrazole ring is not necessary for the key interactions in two proteins.•Phenyl segment at position 4 or 5 of pyrazole ring is important for hydrophobic interactions in both of them.

Heat shock protein90s (Hsp90s) play a crucial role in the development of cancer, and their inhibitors are a main target for tumor suppression. P53 also is a tumor suppressor, but in cancer cells, mutations in the p53 gene lead to the inactivation and accumulation of protein. For instance, the ninth p53 cancer mutation, Y220C, destabilizes the p53 core domain. Small molecules have been assumed to bind to Y220C DNA-binding domain and reactivate cellular mutant p53 functions. In this study, one of the mutant p53 activators is suggested as an Hsp90 inhibitor according to a pyrazole scaffold. To confirm a new ligand as a dual agent, molecular docking and molecular dynamic simulations were performed on both proteins (p53 and Hsp90). Molecular dynamic simulations were also conducted to evaluate the obtained results on the other two pyrazole structures, one known as Hsp90 inhibitor and the other as the reported mutant p53 activator. The findings indicate that the new ligand was stable in the active site of both proteins. Finally, a virtual screening was performed on ZINC database, and a set of new dual agents was proposed according to the new ligand scaffold.

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