Prediction of dual agents as an activator of mutant p53 and inhibitor of Hsp90 by docking,molecular dynamic simulation and virtual screening |
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| Affiliation: | 1. College of Pharmaceutical Science, Zhejiang Chinese Medical University, Hangzhou, Zhejiang 310053, China;2. Academy of Chinese Medical Science, Zhejiang Chinese Medical University, Hangzhou, Zhejiang 310053, China;3. The First Affiliation Hospital, Zhejiang Chinese Medical University, Hangzhou, Zhejiang 310006, China;4. Huzhou Institute for Food and Drug Control, Huzhou 313000, China;5. College of Pharmaceutical Science, Zhejiang University of Technology, Hangzhou, 310014, China;6. Department of Dermatology, Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA;1. Department of Bioscience and Biotechnology, Banasthali University, Banasthali RAJ-304022, India;2. Mason Eye Institute, University of Missouri School of Medicine, Columbia MO-65201, USA;3. Department of Hematology and Medical Oncology, Winship Cancer Institute, Emory University, Atlanta GA-30322, USA;4. Department of Biotechnology, Dravidian University, Kuppam, AP 517 426, India;1. Department of Chemistry, Faculty of Science, Tanta University, Tanta 31527, Egypt;2. Department of Chemistry, Faculty of Science, Damanhour University, Damanhour 31111, Egypt;3. Dipartimento di Chimica Industriale “Toso Montanari”, Università di Bologna, Viale del Risorigmento 4, Bologna 40136, Italy |
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| Abstract: | 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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| Keywords: | Docking Dual agent Hsp90 inhibitors Molecular dynamic simulations P53 Virtual screening |
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