Doddareddy, Munikumar Reddy Thorat, Dhanaji Achyutrao Seo, Seon Hee Hong, Tae-Joon Cho, Yong Seo Hahn, Ji-Sook Pae, Ae Nim 2024-01-20T17:31:26Z 2024-01-20T17:31:26Z 2021-09-02 2011-03-01 0968-0896 https://pubs.kist.re.kr/handle/201004/130543 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 mu M in case of colon cancer (HT29), which is comparable to doxorubicin (0.828 mu M). These compounds were being now used as leads for constructing small molecular libraries to get compounds with favourable pharmacokinetics and drug like properties. (C) 2011 Elsevier Ltd. All rights reserved. English PERGAMON-ELSEVIER SCIENCE LTD HSP90 INHIBITORS PURINE-SCAFFOLD HEAT-SHOCK-PROTEIN-90 IDENTIFICATION GELDANAMYCIN DISCOVERY ISOFORMS BINDING Structure based design of heat shock protein 90 inhibitors acting as anticancer agents Article 10.1016/j.bmc.2011.01.023 1 BIOORGANIC & MEDICINAL CHEMISTRY, v.19, no.5, pp.1714 - 1720 BIOORGANIC & MEDICINAL CHEMISTRY 19 5 1714 1720 scie scopus 000287740200016 2-s2.0-79952188084 Biochemistry & Molecular Biology Chemistry, Medicinal Chemistry, Organic Biochemistry & Molecular Biology Pharmacology & Pharmacy Chemistry Article HSP90 INHIBITORS PURINE-SCAFFOLD HEAT-SHOCK-PROTEIN-90 IDENTIFICATION GELDANAMYCIN DISCOVERY ISOFORMS BINDING HSP90 SBDD Virtual screening Anticancer agents