title: The atom assignment problem in automated de novo drug design. 4. Tests for site-directed fragment placement based on molecular complementarity.
abstract: Three previous papers in this series have outlined an optimization method for atom assignment in drug design using fragment placement. In this paper the procedure is rigorously tested on a selection of five ligand-protein co-crystals. The algorithm is presented with the molecular graph of the ligand, and the electrostatic/hydrophobic potential of the site, with the aim of creating a placement on the molecular graph which is as electrostatically complementary or hydrophobically similar to the site as possible. Various designer options were tested, including, where appropriate, hydrogen bonding and a restricted number of halogens. In most cases, the placement obtained was at least as good as the native ligand, if not significantly better.
authors.affiliation: Department of Pharmacology, University of Cambridge, UK.
authors.forename: M T
authors.initials: MT
authors.lastname: Barakat
authors.forename: P M
authors.initials: PM
authors.lastname: Dean
mesh_terms: D015109:4-Hydroxybenzoate-3-Monooxygenase / Q000737:chemistry / Q000378:metabolism; D000249:Adenosine Monophosphate / Q000378:metabolism; D000263:Adenylate Kinase / Q000737:chemistry / Q000378:metabolism; D000465:Algorithms; D000818:Animals; D001426:Bacterial Proteins / Q000737:chemistry / Q000378:metabolism; D002417:Cattle; D055598:Chemical Phenomena; D002627:Chemistry, Physical; D017076:Computer-Aided Design; D000242:Cyclic AMP / Q000378:metabolism; D002373:Cyclic AMP Receptor Protein / Q000737:chemistry / Q000378:metabolism; D015195:Drug Design; D005492:Folic Acid / Q000378:metabolism; D006801:Humans; D006860:Hydrogen Bonding; D062385:Hydroxybenzoates / Q000378:metabolism; D008024:Ligands; D008958:Models, Molecular; D015394:Molecular Structure; D011487:Protein Conformation; D012177:Retinol-Binding Proteins / Q000737:chemistry / Q000378:metabolism; D013762:Tetrahydrofolate Dehydrogenase / Q000737:chemistry / Q000378:metabolism; D014801:Vitamin A / Q000378:metabolism; D014867:Water
chemical_list: D001426:Bacterial Proteins; D002373:Cyclic AMP Receptor Protein; D062385:Hydroxybenzoates; D008024:Ligands; D012177:Retinol-Binding Proteins; D014867:Water; D014801:Vitamin A; C009091:protocatechuic acid; D000249:Adenosine Monophosphate; D005492:Folic Acid; D000242:Cyclic AMP; D015109:4-Hydroxybenzoate-3-Monooxygenase; D013762:Tetrahydrofolate Dehydrogenase; D000263:Adenylate Kinase