New heat shock protein (Hsp90) inhibitors,designed by pharmacophore modeling and virtual screening: synthesis,biological evaluation and molecular dynamics studies

Abstract

Inhibition of heat shock protein 90 (Hsp90) is known to be a significantly effective strategy in cancer therapy. Here, pyrazolopyranopyrimidine derivatives were characterized as new Hsp90 inhibitors. The molecules’ key structure (ZINC02819805) was determined by utilizing a pharmacophore model virtual screening workflow. Structural optimization was then carried out on compound ZINC02819805, pyrazolopyranopyrimidine derivatives were designed and six chosen derivatives were synthesized. The inhibition of Hsp90 ATPase activity of synthesized compounds revealed that para methylphenyl derivative of pyrazolopyranopyrimidine (HM3) was the most potent inhibitor (IC₅₀ = 5.5?µM). The anti-proliferative activity of this compound was evaluated against a panel of cell lines including MCF-7, HeLa and HUVEC (IC₅₀ = 1.28?µM, IC₅₀ = 1.74?µM and IC₅₀ = 61.48?µM respectively) by MTT method. The western blot analysis of treated MCF-7 cells with compound HM3 showed that the expression level of Hsp70 and Her2 proteins changed. The high level of Hsp70 expression and low level of Her2 expression suggest that compound HM3 exhibits inhibitory effect on Hsp90. Finally, the key interactions between HM3 and Hsp90 protein were studied by molecular dynamics simulation and showed that compound HM3 was stable in Hsp90 active cite during 200?ns simulation. Abbreviations Hsp90 Heat shock protein 90

MTT 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide

ATP adenosine triphosphate

MD molecular dynamics simulation

RMSD root-mean-square deviation

RMSF root-mean-square fluctuation

Rg gyration radius

m-SABNPs boehmite nanoparticles-supported sulfamic acid

Communicated by Ramaswamy H. Sarma