title: Homology modeling and virtual screening approaches to identify potent inhibitors of slingshot phosphatase 1.
abstract: Although slingshot phosphatase 1 (SSH1) proved to be a promising target for the development of therapeutics for the treatment of vascular diseases and cancers, no small-molecule inhibitor has been reported so far. We have been able to identify eight novel inhibitors of SSH1 through the computer-aided drug design protocol involving homology modeling of SSH1 structure, virtual screening of a large chemical library with docking simulations, and in vitro enzyme assays. The identified inhibitors revealed high potencies with the associated IC(50) values ranging from 2.8 to 12.7μM and were also screened for having desirable physicochemical properties as a drug candidate. Therefore, they deserve consideration for further development by structure-activity relationship studies to optimize the inhibitory activities. Structural features relevant to the stabilization of the inhibitors in the active site of SSH1 are discussed in detail.
authors.affiliation: Department of Bioscience and Biotechnology, Sejong University, 98 Kunja-Dong, Kwangjin-Ku, Seoul, South Korea. hspark@sejong.ac.kr
authors.forename: Hwangseo
authors.initials: H
authors.lastname: Park
authors.forename: So Ya
authors.initials: SY
authors.lastname: Park
authors.forename: Seong Eon
authors.initials: SE
authors.lastname: Ryu
mesh_terms: D000465:Algorithms; D000595:Amino Acid Sequence; D001665:Binding Sites; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology; D008958:Models, Molecular; D062105:Molecular Docking Simulation; D008969:Molecular Sequence Data; D010749:Phosphoprotein Phosphatases / Q000037:antagonists & inhibitors / Q000737:chemistry*; D011485:Protein Binding; D016415:Sequence Alignment; D013329:Structure-Activity Relationship
chemical_list: D004791:Enzyme Inhibitors; D010749:Phosphoprotein Phosphatases