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

Christophe L.M.J. Verlinde*, Gabrielle Rudenko, Wim G.J. Hol

*Corresponding author for this work

    Research output: Contribution to journalArticleAcademicpeer-review

    73 Citations (Scopus)

    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.

    Original languageEnglish
    Pages (from-to)131-147
    Number of pages17
    JournalJournal of Computer-Aided Molecular Design
    Volume6
    Issue number2
    DOIs
    Publication statusPublished - Apr-1992

    Keywords

    • MODULAR STRUCTURE-BASED INHIBITOR DESIGN
    • CHEMICAL DATABASE
    • TRIOSEPHOSPHATE ISOMERASE
    • TRIOSE-PHOSPHATE ISOMERASE
    • GLYCOSOMAL TRIOSEPHOSPHATE ISOMERASE
    • FAVORABLE BINDING-SITES
    • BRUCEI-BRUCEI
    • RECOGNITION
    • RESOLUTION
    • DEFICIENCY
    • ENZYMES
    • MUSCLE

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