title: An in silico structure-based approach to anti-infective drug discovery.
abstract: In light of the low success rate of target-based genomics and HTS (High Throughput Screening) approaches in anti-infective drug discovery, in silico structure-based drug design (SBDD) is becoming increasingly prominent at the forefront of drug discovery. In silico SBDD can be used to identify novel enzyme inhibitors rapidly, where the strength of this approach lies with its ability to model and predict the outcome of protein-ligand binding. Over the past 10 years, our group have applied this approach to a diverse number of anti-infective drug targets ranging from bacterial D-ala-D-ala ligase to Plasmodium falciparum DHODH. Our search for new inhibitors has produced lead compounds with both enzyme and whole-cell activity with established on-target mode of action. This has been achieved with greater speed and efficiency compared with the more traditional HTS initiatives and at significantly reduced cost and manpower.
authors.affiliation: School of Chemistry, University of Leeds, Leeds, UK.
authors.forename: Fraser
authors.initials: F
authors.lastname: Cunningham
authors.affiliation: School of Chemistry, University of Leeds, Leeds, UK.
authors.forename: Martin J
authors.initials: MJ
authors.lastname: McPhillie
authors.affiliation: School of Chemistry, University of Leeds, Leeds, UK.
authors.forename: A Peter
authors.initials: AP
authors.lastname: Johnson
authors.affiliation: School of Chemistry, University of Leeds, Leeds, UK.
authors.forename: Colin W G
authors.initials: CW
authors.lastname: Fishwick
mesh_terms: D000890:Anti-Infective Agents / Q000737:chemistry* / Q000494:pharmacology; D001424:Bacterial Infections / Q000188:drug therapy / Q000382:microbiology; D000090722:Dihydroorotate Dehydrogenase; D015195:Drug Design; D055808:Drug Discovery; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000494:pharmacology; D057166:High-Throughput Screening Assays / Q000191:economics / Q000706:statistics & numerical data; D006801:Humans; D008024:Ligands; D016778:Malaria, Falciparum / Q000188:drug therapy / Q000469:parasitology; D062105:Molecular Docking Simulation; D044925:Oxidoreductases Acting on CH-CH Group Donors / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D010453:Peptide Synthases / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D015800:Protozoan Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D014584:User-Computer Interface
chemical_list: D000890:Anti-Infective Agents; D000090722:Dihydroorotate Dehydrogenase; D004791:Enzyme Inhibitors; D008024:Ligands; D015800:Protozoan Proteins; D044925:Oxidoreductases Acting on CH-CH Group Donors; D010453:Peptide Synthases; C019638:D-alanylalanine synthetase