Receptor-ligand interaction-based virtual screening for novel Eg5/kinesin spindle protein inhibitors.
Eg5/KSP is a promising mitotic spindle target for drug discovery in cancer chemotherapy and the development of agents against fungal diseases. A range of Eg5 targeting compounds identified by in vitro or cell-based screening is currently in development. We employed structure-based virtual screening of a database of 700, 000 compounds to identify three novel Eg5 inhibitors bearing quinazoline (24) or thioxoimidazolidine (30 and 37) scaffolds. The new compounds inhibit Eg5 ATPase activity, show growth inhibition in proliferation assays, and induce monoastral spindles in cells, the characteristic phenotype for Eg5 inhibiting agents. This is the first successful reported procedure for the identification of Eg5 inhibitors via receptor-ligand interaction-based virtual screening.
Neuro-Medicine Center, Life Sciences Division, Korea Institute of Science and Technology, PO Box 131, Cheongryang, Seoul 130-650, Republic of Korea.
Shanthi
S
Nagarajan
Dimitrios A
DA
Skoufias
Frank
F
Kozielski
Ae Nim
AN
Pae
D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D016208:Databases, Factual; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D048289:Imidazolidines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D016547:Kinesins / Q000037:antagonists & inhibitors* / Q000737:chemistry; D008024:Ligands; D008958:Models, Molecular; D011485:Protein Binding; D011799:Quinazolines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D008941:Spindle Apparatus / Q000187:drug effects; D013329:Structure-Activity Relationship
D000970:Antineoplastic Agents; D048289:Imidazolidines; C470243:KIF11 protein, human; D008024:Ligands; D011799:Quinazolines; D016547:Kinesins