Structure based design of heat shock protein 90 inhibitors acting as anticancer agents
- Structure based design of heat shock protein 90 inhibitors acting as anticancer agents
- 무니크말레디; 또라트; 서선희; 홍태훈; 조용서; 한지숙; 배애님
- HSP90; anticancer; 항암제; SBDD; Virtual screening; Anticancer agents
- Issue Date
- Bioorganic & medicinal chemistry
- VOL 19, NO 5, 1714-1720
- Structure based drug design (SBDD) was used to discover heat shock protein 90 (HSP90) inhibitors useful
in the treatment of cancer. By using the crystal structure of HSP90–ligand complex (1uyi), a docking
model was prepared and was validated by external dataset containing known HSP90 inhibitors. This validated
model was then used to virtually screen commercial databases, selected hits of which were bought
and sent for real biological evaluation. Further as an alternative method, pharmacophores were generated
using crystal structure conformations of ligands in HSP90 complexes (1uyi and 2bz5) and where used for
virtual screening. Both cases yielded several hits containing novel scaffolds, particularly compound
KHSP8 showed an IC50 value of 0.902 lM in case of colon cancer (HT29), which is comparable to doxorubicin
(0.828 μM). These compounds were being now used as leads for constructing small molecular
libraries to get compounds with favourable pharmacokinetics and drug like properties.
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