Discovery of Novel Hsp90 Inhibitors Bearing 2H-Triazole Ring

9 TH INTERNATIONAL BAU DRUG DESIGN CONGRESS, İstanbul, Türkiye, 29 Kasım - 02 Aralık 2023, ss.50, (Özet Bildiri)

Introduction: Hsp90 is an evolutionarily conserved molecular chaperone in eukaryotes that

modulates multiple cellular processes through signaling pathways regulated by Hsp90-

related proteins such as proliferation, cell cycle, and gene expression. Therefore, targeting

Hsp90 today is a promising strategy for developing a new anticancer drug.

Methods: In the present work, structure- based approaches were used for virtual screening

of a library of ~1000000 compounds (containing 2H-triazole ring), which was downloaded

from ZINC-15 database. GLIDE modules such as HTVS (high throughput virtual screening),

SP (Standard precision) and XP (Extra precision) were used as molecular docking tools for

virtual screening. The ADME (absorption, distribution, metabolism, and excretion)

properties of the best Glide XP compounds were evaluated, and elimination was made based

on the #stars values. The remaining complexes were then examined by molecular dynamics

simulations using Desmond.

Results and Discussion: Hit compounds (ZINC000286820133, ZINC000286803821,

ZINC000286977413 and ZINC000286894825) were determined as a result of virtual

screening and ADME, and molecular dynamics simulations (200 ns) of Hsp-90-hit complexes

were carried out. The findings revealed that hit compounds were stable in the binding

pocket.

Conclusions: The stable HSP90-hit complexes were discovered in this study, and the hit

molecules were computationally determined to be potential Hsp90 inhibitors. In the wet lab,

the anticancer effects and HSP90 protein interactions of the hit compounds will be

examined in the wet lab.

TÜBİTAK (Project number: 221Z272) funded this research.

Keywords: Hsp90, Virtual Screening, Molecular Simulation