title: Identification of non-lipid LPA3 antagonists by virtual screening.
abstract: In the present study, we utilized virtual screening to identify LPA(3) antagonists. We have developed a three-point structure-based pharmacophore model based on known LPA(3) antagonists. This model was used to mine the NCI database. Docking, pharmacophore development, and database mining produced new, non-lipid leads. Experimental testing of seven computationally selected pharmacophore hits produced one potentiator and three antagonists, one of which displays both LPA(3) selectivity and nanomolar potency. Similarity searching in the ChemBridge database using the most promising lead as the search target produced four additional LPA(3) antagonists and a potent dual LPA(1&2) antagonist.
authors.affiliation: Department of Chemistry and Computational Research on Materials Institute, The University of Memphis, Memphis, TN 38152, USA.
authors.forename: James I
authors.initials: JI
authors.lastname: Fells
authors.forename: Ryoko
authors.initials: R
authors.lastname: Tsukahara
authors.forename: Yuko
authors.initials: Y
authors.lastname: Fujiwara
authors.forename: Jianxiong
authors.initials: J
authors.lastname: Liu
authors.forename: Donna H
authors.initials: DH
authors.lastname: Perygin
authors.forename: Daniel A
authors.initials: DA
authors.lastname: Osborne
authors.forename: Gabor
authors.initials: G
authors.lastname: Tigyi
authors.forename: Abby L
authors.initials: AL
authors.lastname: Parrill
mesh_terms: D000818:Animals; D016466:CHO Cells; D002118:Calcium / Q000737:chemistry / Q000378:metabolism; D020013:Calcium Signaling / Q000502:physiology; D002417:Cattle; D045744:Cell Line, Tumor; D003198:Computer Simulation; D006224:Cricetinae; D003412:Cricetulus; D004075:Diglycerides / Q000737:chemistry / Q000494:pharmacology; D007555:Isoxazoles / Q000737:chemistry / Q000494:pharmacology; D008246:Lysophospholipids / Q000819:agonists / Q000037:antagonists & inhibitors* / Q000378:metabolism; D008956:Models, Chemical; D008958:Models, Molecular; D011422:Propionates / Q000737:chemistry / Q000494:pharmacology; D020033:Protein Isoforms / Q000037:antagonists & inhibitors / Q000378:metabolism; D051381:Rats; D049368:Receptors, Lysophosphatidic Acid / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics; D012243:Rhodopsin / Q000737:chemistry; D040681:Structural Homology, Protein
chemical_list: C477898:3-(4-(4-((1-(2-chlorophenyl)ethoxy)carbonyl amino)-3-methyl-5-isoxazolyl) benzylsulfanyl) propanoic acid; D004075:Diglycerides; D007555:Isoxazoles; D008246:Lysophospholipids; D011422:Propionates; D020033:Protein Isoforms; D049368:Receptors, Lysophosphatidic Acid; D012243:Rhodopsin; C032881:lysophosphatidic acid; D002118:Calcium