title: Structure based design of heat shock protein 90 inhibitors acting as anticancer agents.
abstract: 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 IC(50) value of 0.902 μM 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.
authors.affiliation: Neuro-Medicine Center, Korea Institute of Science and Technology, Seoul, Republic of Korea.
authors.forename: Munikumar Reddy
authors.initials: MR
authors.lastname: Doddareddy
authors.forename: Dhanaji Achyutrao
authors.initials: DA
authors.lastname: Thorat
authors.forename: Seon Hee
authors.initials: SH
authors.lastname: Seo
authors.forename: Tae-Joon
authors.initials: TJ
authors.lastname: Hong
authors.forename: Yong Seo
authors.initials: YS
authors.lastname: Cho
authors.forename: Ji-Sook
authors.initials: JS
authors.lastname: Hahn
authors.forename: Ae Nim
authors.initials: AN
authors.lastname: Pae
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D003110:Colonic Neoplasms / Q000473:pathology; D015195:Drug Design; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors*; D006801:Humans; D020128:Inhibitory Concentration 50; D008958:Models, Molecular; D015394:Molecular Structure
chemical_list: D000970:Antineoplastic Agents; D018841:HSP90 Heat-Shock Proteins