title: Virtual screening and biochemical evaluation to identify new inhibitors of mammalian target of rapamycin (mTOR).
abstract: Mammalian target of rapamycin (mTOR) is a promising target for the development of anticancer medicines. Here, we report the first example for a successful application of the structure-based virtual screening to identify new mTOR inhibitors. Using the scoring function improved by implementing the ligand solvation effects on protein-ligand association, six novel mTOR inhibitors are found with IC50 values ranging from 8 to 60 μM. Because these new inhibitors are also computationally screened for having desirable physicochemical properties as a drug candidate, they deserve consideration for further development by structure-activity relationship studies to optimize the inhibitory and anticancer activities. Structural features relevant to the stabilization of the inhibitors in the ATP-binding site of mTOR are addressed in detail.
authors.affiliation: Department of Bioscience and Biotechnology, Sejong University, 98 Kunja-Dong, Kwangjin-Ku, Seoul 143-747, Republic of Korea. Electronic address: hspark@sejong.ac.kr.
authors.forename: Hwangseo
authors.initials: H
authors.lastname: Park
authors.affiliation: Department of Chemistry, Korea Advanced Institute of Science and Technology (KAIST), Daejeon 305-701, Republic of Korea.
authors.forename: Hyeonjeong
authors.initials: H
authors.lastname: Choe
authors.affiliation: Department of Chemistry, Korea Advanced Institute of Science and Technology (KAIST), Daejeon 305-701, Republic of Korea. Electronic address: hongorg@kaist.ac.kr.
authors.forename: Sungwoo
authors.initials: S
authors.lastname: Hong
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D003198:Computer Simulation; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D020128:Inhibitory Concentration 50; D008958:Models, Molecular; D011485:Protein Binding / Q000187:drug effects; D055550:Protein Stability / Q000187:drug effects; D013329:Structure-Activity Relationship; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors*
chemical_list: D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; C546842:MTOR protein, human; D058570:TOR Serine-Threonine Kinases
keywords: Anticancer agents; Docking; Kinase inhibitor; Virtual screening; mTOR