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 output: Contribution to journalArticle

70 Scopus citations

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 (US)
Pages (from-to)131-147
Number of pages17
JournalJournal of Computer-Aided Molecular Design
Volume6
Issue number2
DOIs
StatePublished - Apr 1 1992
Externally publishedYes

Keywords

  • Chemical database
  • Modular structure-based inhibitor design
  • Triosephosphate isomerase

ASJC Scopus subject areas

  • Drug Discovery
  • Computer Science Applications
  • Physical and Theoretical Chemistry

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