Repository of Research and Investigative Information

Repository of Research and Investigative Information

Hormozgan University of Medical Sciences

New heat shock protein (Hsp90) inhibitors, designed by pharmacophore modeling and virtual Screening: Synthesis, Biological evaluation and molecular dynamics studies.

(2019) New heat shock protein (Hsp90) inhibitors, designed by pharmacophore modeling and virtual Screening: Synthesis, Biological evaluation and molecular dynamics studies. J Biomol Struct Dyn..

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Official URL: https://www.ncbi.nlm.nih.gov/pubmed/31452440

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 keys interactions between HM3 and Hsp90 protein were studied by molecular dynamic simulation and showed that compound HM3 was stable in Hsp90 active cite during 200ns simulation.

Item Type: Article
Keywords: Hsp90 inhibitors; Molecular dynamic simulation; Pharmacophore modeling; Pyrazolopyranopyrimidine; Western blot
Subjects: QU Biochemistry. Cell Biology and Genetics > QU 100-133 Biochemistry of the Human Body
QU Biochemistry. Cell Biology and Genetics > QU 300-560 Cell Biology and Genetics
Depositing User: هدی فهیم پور
URI: http://eprints.hums.ac.ir/id/eprint/6616

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