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. © 1992 ESCOM Science Publishers B.V.
CITATION STYLE
Verlinde, C. L. M. J., Rudenko, G., & Hol, W. G. J. (1992). In search of new lead compounds for trypanosomiasis drug design: A protein structure-based linked-fragment approach. Journal of Computer-Aided Molecular Design, 6(2), 131–147. https://doi.org/10.1007/BF00129424
Mendeley helps you to discover research relevant for your work.