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Journal of Computer-Aided Molecular Design

, Volume 6, Issue 2, pp 131–147 | Cite as

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
Research Papers

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.

Key words

Modular structure-based inhibitor design Chemical database Triosephosphate isomerase 

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Copyright information

© ESCOM Science Publishers B.V 1992

Authors and Affiliations

  • Christophe L. M. J. Verlinde
    • 1
  • Gabrielle Rudenko
    • 1
  • Wim G. J. Hol
    • 1
  1. 1.BIOSON Research InstituteUniversity of GroningenGroningenThe Netherlands

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