title: LEA3D: a computer-aided ligand design for structure-based drug design.
abstract: We present an improved version of the program LEA developed to design organic molecules. Rational drug design involves finding solutions to large combinatorial problems for which an exhaustive search is impractical. Genetic algorithms provide a tool for the investigation of such problems. New software, called LEA3D, is now able to conceive organic molecules by combining 3D fragments. Fragments were extracted from both biological compounds and known drugs. A fitness function guides the search process in optimizing the molecules toward an optimal value of the properties. The fitness function is build up by combining several independent property evaluations, including the score provided by the FlexX docking program. One application in de novo drug design is described. The example makes use of the structure of Mycobacterium tuberculosis thymidine monophosphate kinase to generate analogues of one of its natural substrates. Among 22 tested compounds, 17 show inhibitory activity in the micromolar range.
authors.affiliation: Centre de Biochimie Structurale (CNRS UMR 5048, INSERM UMR U554), Faculté de Pharmacie, Université Montpellier I, 15, avenue Charles Flahault, 34060 Montpellier Cedex, France. douguet@cbs.cnrs.fr
authors.forename: Dominique
authors.initials: D
authors.lastname: Douguet
authors.forename: Hélène
authors.initials: H
authors.lastname: Munier-Lehmann
authors.forename: Gilles
authors.initials: G
authors.lastname: Labesse
authors.forename: Sylvie
authors.initials: S
authors.lastname: Pochet
mesh_terms: D000465:Algorithms; D001665:Binding Sites; D017076:Computer-Aided Design; D016208:Databases, Factual; D015195:Drug Design; D008024:Ligands; D008958:Models, Molecular; D009169:Mycobacterium tuberculosis / Q000737:chemistry; D009703:Nucleoside-Phosphate Kinase / Q000037:antagonists & inhibitors / Q000737:chemistry; D011485:Protein Binding; D011506:Proteins / Q000737:chemistry*; D012984:Software
chemical_list: D008024:Ligands; D011506:Proteins; D009703:Nucleoside-Phosphate Kinase; C020093:dTMP kinase