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

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Summary

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.

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Authors and Affiliations

  1. BIOSON Research Institute, University of Groningen, Nijenborgh 4, 9747 AG, Groningen, The Netherlands

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

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  1. Christophe L. M. J. Verlinde
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  2. Gabrielle Rudenko
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  3. Wim G. J. Hol
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Verlinde, C.L.M.J., Rudenko, G. & Hol, W.G.J. In search of new lead compounds for trypanosomiasis drug design: A protein structure-based linked-fragment approach. J Computer-Aided Mol Des 6, 131–147 (1992). https://doi.org/10.1007/BF00129424

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