Structural aspects of triazole derivatives as HSP90 inhibitors for the treatment of cancer: in silico studies.

Abstract

HSP90, one important class of chaperons has been intensively investigated as a promising and novel class of drug target for cancer therapy from the past few decades. A series of 2-((4-resorcinolyl)-5-aryl-1, 2, 3-triazol-1-yl) acetate derivatives were taken in the present study for the generation of pharmacophore based models, predictive 3 D-QSAR models, docking and ZINC screening studies against HSP90. The investigation included 30 ligands which emerged DHRRR_1 having survival score of 5.59 was found the most effective pharmacophore model. The generated third PLS factor includes a model with significant Q2, R2, and R2 CV values as 0.62, 0.77, and 0.50, respectively. The molecular docking studies against HSP90 showed interactions with important amino acids such as GLY-97, ASN-106, THR-184, ASN-51, PHE-138 and SER-52 required for HSP90 inhibitory activity. According to the docking analysis compound 34 was the top scoring compound, had a docking score of -10.98 from the series and showed interactions with amino acids likeASP-93, GLY-97, AND ASP-102. Using pharmacophore characteristics, the virtual screening investigation was carried out and DHRRR_1 showed the potential ZINC compounds. The ZINC compounds ZINC72417069 and ZINC77522480 showed best XP docking scores (-8.205 and -7.103 consecutively) and the top-scoring compound ZINC72417069 displayed amino acid binding affinity with GLY-97, ASN-106, and THR-184 against HSP90, PDB ID: 2xjx. These ZINC compounds can be used as target for HSP90. The result of the study may further help to the scientist for the design and development of potential HSP90 inhibitors.

• Authors: Shubham Dhiman, Moumita Saha, Amena Ali, Abuzer Ali, G D Gupta, Vivek Asati
• Journal: Journal of biomolecular structure & dynamics (J Biomol Struct Dyn) Vol. 41 Issue 10 Pg. 4756-4769 (Jul 2023) ISSN: 1538-0254 [Electronic] England
• PMID: 35665636 (Publication Type: Journal Article)

Chemical References

• Antineoplastic Agents
• HSP90 Heat-Shock Proteins
• Amino Acids
• Triazoles

Topics

• Molecular Docking Simulation
• Quantitative Structure-Activity Relationship
• Antineoplastic Agents (pharmacology, chemistry)
• HSP90 Heat-Shock Proteins
• Amino Acids
• Triazoles (pharmacology)
• Neoplasms