title: A Teach-Discover-Treat Application of ZincPharmer: An Online Interactive Pharmacophore Modeling and Virtual Screening Tool.
abstract: The 2012 Teach-Discover-Treat (TDT) community-wide experiment provided a unique opportunity to test prospective virtual screening protocols targeting the anti-malarial target dihydroorotate dehydrogenase (DHODH). Facilitated by ZincPharmer, an open access online interactive pharmacophore search of the ZINC database, the experience resulted in the development of a novel classification scheme that successfully predicted the bound structure of a non-triazolopyrimidine inhibitor, as well as an overall hit rate of 27% of tested active compounds from multiple novel chemical scaffolds. The general approach entailed exhaustively building and screening sparse pharmacophore models comprising of a minimum of three features for each bound ligand in all available DHODH co-crystals and iteratively adding features that increased the number of known binders returned by the query. Collectively, the TDT experiment provided a unique opportunity to teach computational methods of drug discovery, develop innovative methodologies and prospectively discover new compounds active against DHODH.
authors.affiliation: Department of Computational and Systems Biology, University of Pittsburgh, Pittsburgh, PA, United States of America.
authors.forename: David Ryan
authors.initials: DR
authors.lastname: Koes
authors.affiliation: Department of Computational and Systems Biology, University of Pittsburgh, Pittsburgh, PA, United States of America.
authors.forename: Nicolas A
authors.initials: NA
authors.lastname: Pabon
authors.affiliation: Department of Pharmacology, University of Texas Southwestern Medical Center at Dallas, 6001 Forest Park Blvd, Dallas, TX, United States of America.
authors.forename: Xiaoyi
authors.initials: X
authors.lastname: Deng
authors.affiliation: Department of Pharmacology, University of Texas Southwestern Medical Center at Dallas, 6001 Forest Park Blvd, Dallas, TX, United States of America.
authors.forename: Margaret A
authors.initials: MA
authors.lastname: Phillips
authors.affiliation: Department of Computational and Systems Biology, University of Pittsburgh, Pittsburgh, PA, United States of America.
authors.forename: Carlos J
authors.initials: CJ
authors.lastname: Camacho
mesh_terms: D000962:Antimalarials / Q000494:pharmacology*; D003460:Crystallization; D000090722:Dihydroorotate Dehydrogenase; D015195:Drug Design; D055808:Drug Discovery; D020407:Internet; D007700:Kinetics; D008024:Ligands; D008288:Malaria / Q000188:drug therapy; D062105:Molecular Docking Simulation; D044925:Oxidoreductases Acting on CH-CH Group Donors / Q000737:chemistry; D011485:Protein Binding; D011487:Protein Conformation
chemical_list: D000962:Antimalarials; D000090722:Dihydroorotate Dehydrogenase; D008024:Ligands; D044925:Oxidoreductases Acting on CH-CH Group Donors