title: In search of new lead compounds for trypanosomiasis drug design: a protein structure-based linked-fragment approach.
abstract: A modular method for pursuing structure-based inhibitor design in the framework of a design cycle is presented. The approach entails four stages: (1) a design pathway is defined in the three-dimensional structure of a target protein; (2) this pathway is divided into subregions; (3) complementary building blocks, also called fragments, are designed in each subregion; complementarity is defined in terms of shape, hydrophobicity, hydrogen bond properties and electrostatics; and (4) fragments from different subregions are linked into potential lead compounds. Stages (3) and (4) are qualitatively guided by force-field calculations. In addition, the designed fragments serve as entries for retrieving existing compounds from chemical databases. This linked-fragment approach has been applied in the design of potentially selective inhibitors of triosephosphate isomerase from Trypanosoma brucei, the causative agent of sleeping sickness.
authors.affiliation: BIOSON Research Institute, University of Groningen, The Netherlands.
authors.forename: C L
authors.initials: CL
authors.lastname: Verlinde
authors.forename: G
authors.initials: G
authors.lastname: Rudenko
authors.forename: W G
authors.initials: WG
authors.lastname: Hol
mesh_terms: D000818:Animals; D001665:Binding Sites; D016208:Databases, Factual; D015195:Drug Design; D006801:Humans; D007854:Lead / Q000737:chemistry*; D008958:Models, Molecular; D015394:Molecular Structure; D009942:Organometallic Compounds / Q000737:chemistry; D011506:Proteins / Q000737:chemistry; D014305:Triose-Phosphate Isomerase / Q000037:antagonists & inhibitors / Q000737:chemistry; D014344:Trypanocidal Agents / Q000737:chemistry*; D014345:Trypanosoma / Q000187:drug effects / Q000201:enzymology; D014352:Trypanosomiasis / Q000188:drug therapy
chemical_list: D009942:Organometallic Compounds; D011506:Proteins; D014344:Trypanocidal Agents; D007854:Lead; D014305:Triose-Phosphate Isomerase