Structure-based inhibitor design by using protein models for the development of antiparasitic agents

Proc Natl Acad Sci U S A. 1993 Apr 15;90(8):3583-7. doi: 10.1073/pnas.90.8.3583.


The lack of an experimentally determined structure of a target protein frequently limits the application of structure-based drug design methods. In an effort to overcome this limitation, we have investigated the use of computer model-built structures for the identification of previously unknown inhibitors of enzymes from two major protease families, serine and cysteine proteases. We have successfully used our model-built structures to identify computationally and to confirm experimentally the activity of nonpeptidic inhibitors directed against important enzymes in the schistosome [2-(4-methoxybenzoyl)-1-naphthoic acid, Ki = 3 microM] and malaria (oxalic bis[(2-hydroxy-1-naphthylmethylene)hydrazide], IC50 = 6 microM) parasite life cycles.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Anti-Infective Agents / chemistry*
  • Antimalarials / chemistry
  • Antimalarials / pharmacology
  • Drug Design
  • Endopeptidases / chemistry*
  • Endopeptidases / metabolism
  • Models, Molecular
  • Molecular Conformation
  • Pancreatic Elastase / chemistry
  • Plasmodium falciparum / drug effects
  • Plasmodium falciparum / physiology
  • Protease Inhibitors / chemistry*
  • Protein Conformation
  • Schistosoma / drug effects
  • Schistosoma / physiology
  • Schistosomicides / chemistry
  • Schistosomicides / pharmacology
  • Structure-Activity Relationship


  • Anti-Infective Agents
  • Antimalarials
  • Protease Inhibitors
  • Schistosomicides
  • Endopeptidases
  • Pancreatic Elastase