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    J Comput Aided Mol Des. 1992 Apr;6(2):131-47.

    In search of new lead compounds for trypanosomiasis drug design: a protein structure-based linked-fragment approach.

    Source

    BIOSON Research Institute, University of Groningen, The Netherlands.

    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.

    PMID:
    1624956
    [PubMed - indexed for MEDLINE]

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