Prediction of dual agents as an activator of mutant p53 and inhibitor of Hsp90 by docking, molecular dynamic simulation and virtual screening.
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.
Department of Medicinal Chemistry, Faculty of Pharmacy, Isfahan University of Medical Sciences, 81746-73461 Isfahan, Iran; Department of Medicinal Chemistry, Faculty of Pharmacy, Pharmaceutical Science Research Center, Tehran University of Medical Science, Tehran, Iran. Electronic address: mabbasi@pharm.mui.ac.ir.
Maryam
M
Abbasi
Department of Medicinal Chemistry, Faculty of Pharmacy, Isfahan University of Medical Sciences, 81746-73461 Isfahan, Iran. Electronic address: sadeghi@pharm.mui.ac.ir.
Hojjat
H
Sadeghi-Aliabadi
Department of Medicinal Chemistry, Faculty of Pharmacy, Isfahan University of Medical Sciences, 81746-73461 Isfahan, Iran.
Farshid
F
Hassanzadeh
Department of Medicinal Chemistry, Faculty of Pharmacy, Pharmaceutical Science Research Center, Tehran University of Medical Science, Tehran, Iran. Electronic address: amanlou@tums.ac.ir.
Massoud
M
Amanlou
D020816:Amino Acid Motifs; D000970:Antineoplastic Agents / Q000737:chemistry*; D020134:Catalytic Domain; D055808:Drug Discovery; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry; D057166:High-Throughput Screening Assays; D006801:Humans; D008024:Ligands; D062105:Molecular Docking Simulation; D056004:Molecular Dynamics Simulation; D008969:Molecular Sequence Data; D009154:Mutation; D011485:Protein Binding; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D011720:Pyrazoles / Q000737:chemistry*; D013329:Structure-Activity Relationship; D013816:Thermodynamics; D016159:Tumor Suppressor Protein p53 / Q000819:agonists* / Q000737:chemistry; D014584:User-Computer Interface
D000970:Antineoplastic Agents; D018841:HSP90 Heat-Shock Proteins; D008024:Ligands; D011720:Pyrazoles; D016159:Tumor Suppressor Protein p53
Docking; Dual agent; Hsp90 inhibitors; Molecular dynamic simulations; P53; Virtual screening