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

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

Fingerprint

Chemical Databases
Triose-Phosphate Isomerase
Lead compounds
lead compounds
Trypanosoma brucei brucei
Trypanosomiasis
Drug Design
Static Electricity
Hydrophobic and Hydrophilic Interactions
Hydrogen
drugs
fragments
proteins
Proteins
Pharmaceutical Preparations
inhibitors
sicknesses
Hydrophobicity
hydrophobicity
entry

Keywords

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

ASJC Scopus subject areas

  • Molecular Medicine

Cite this

In search of new lead compounds for trypanosomiasis drug design : A protein structure-based linked-fragment approach. / Verlinde, Christophe L M J; Rudenko, Gabrielle; Hol, Wim G J.

In: Journal of Computer-Aided Molecular Design, Vol. 6, No. 2, 04.1992, p. 131-147.

Research output: Contribution to journalArticle

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