Designing HSP90 inhibitor drugs against mutations profiles of cancer patients
Department of Molecular Medicine, Aziz Sancar Institute of Experimental Medicine, Istanbul University, Istanbul, Turkey.
Research Article
International Journal of Frontiers in Biology and Pharmacy Research, 2021, 01(02), 008–012.
Article DOI: 10.53294/ijfbpr.2021.1.2.0045
Publication history:
Received on 13 October 2021; revised on 01 December 2021; accepted on 03 December 2021
Abstract:
Background: Effective drug binding to its specific receptor determines the therapeutic effect. Tumor cells employ Heat Shock Protein 90 (Hsp90) to survive as Hsp90 prevents apoptosis. The protein is the top expressed protein among others. This expression rate further increases in tumor cells and provides a fine target for drug design. However, mutations and copy number variations, single nucleotide polymorphisms of the target gene as well as strong binding of therapeutic agents to the target provide adverse effects.
Aims: This work investigates HSP90 interaction with common inhibitor geldanamycin through key mutations to understand possible effects.
Methods: In silico analysis by YASARA software was employed to reveal interactions between HSP90 WT and its mutant along with geldanamycin.
Results: One key inhibitor-resistant critical residue interaction was monitored for each cytosolic HSP90 isoform. The residues are at critical positions during conformational changes and at the mutated regions of the protein. However, finely designed geldanamycin still tolerates its binding to HSP90.
Conclusion: HSP has no introns and may seem non-mutable, but designing inhibitors by considering structural alterations increases the effectiveness of the drug candidates and limits side effects through in silico experiments.
Keywords:
HSP90; Geldanamycin; in silico; Cancer
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Copyright © 2021 Author(s) retain the copyright of this article. This article is published under the terms of the Creative Commons Attribution Liscense 4.0