In-Silico Study for Potential Inhibitors of Both HSP72 and HSC70 Proteins in the Treatment of Cancer

Abstract

HSP90 (Heat shock protein 90), molecular chaperone contains various oncogenic client proteins, which play a significant role in initiating cancer cell hallmarks. The “HSP90-addiction” of cancer cells, makes it a suitable target in cancer treatment. Inhibition of HSP90 mitigates the tumor progression but results in over-expression of the HSP70 family (The 70-kDa heat shock proteins). HSP70 family is expressed abundantly in human tumors. High expression of HSP70 in cancer cells is responsible for tumor progression. It has been found that, inhibition of both Heat shock 70 kDa protein 1a, HSP72 and Heat shock cognate 71-kDa proteins and HSC70 (two isoforms of the HSP70 family) simultaneously lead to the inhibition of HSP90 client proteins. In this study, molecular docking approach was done in search of the best possible inhibitors of HSP72 and HSC70. Zafirlukast was used as a reference drug that is a potent inhibitor of both the isoforms HSP72 and HSC70. The binding affinity of Zafirlukast with HSP72 (PDB ID-5AQZ) and HSC70 (PDB ID-4H5N) is -10.5 and -9.9 kcal/mol respectively. 100 potential inhibitors (Anti-diabetic drugs, anti-rheumatic drugs, anti-inflammatory, statins and small molecule inhibitors) were screened through In silico approach and Apoptozole was found to be a potential inhibitor of both HSP72 and HSC70 with strong binding affinities of -11.0 and -10.2 kcal/mol respectively. Protein-ligand interaction was monitored and visualized by discovery studio to better understand the nature of intermolecular bonds. Furthermore, ADMET properties were obtained from admetSAR 2.0 and were compared with reference drug for validation.