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 language | English |
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Pages (from-to) | 131-147 |
Number of pages | 17 |
Journal | Journal of Computer-Aided Molecular Design |
Volume | 6 |
Issue number | 2 |
DOIs | |
Publication status | Published - 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