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From Inhibitors of Lap to Inhibitors of Pal

  • Łukasz Berlicki
  • Jolanta Grembecka
  • Edyta Dyguda-Kazimierowicz
  • PaweŁ Kafarski
  • W. Andrzej Sokalski
Part of the Challenges and Advances in Computational Chemistry and Physics book series (COCH, volume 4)

Abstract

Computer-aided techniques of rational design of enzyme inhibitors were reviewed. In silico lead generation and optimization protocols were outlined and several methods of inhibitor potency estimation by both empirical scoring functions as well as ab initio based calculations were described. Two representative examples of successful computer-aided analysis and design of novel, highly potent inhibitors of leucine aminopeptidase and glutamine synthetase were demonstrated. In addition fully nonempirical and systematic analysis of the physical nature of enzyme active site interactions has been performed for series of leucine aminopeptidase (LAP) and phenylalanine ammonia lyase (PAL) inhibitors. Results derived from ab initio calculations indicate that inhibitory activity is controlled by interactions with limited number of active site residues. Examination of entire hierarchy of theoretical models indicates that the inhibitory activity could be well represented by electrostatic interactions, leading to so called ‘‘electrostatic key-lock’’ principle

Keywords

Drug design molecular modeling agrochemicals enzyme inhibitors ab initio intermolecular interactions leucine aminopeptidase glutamine synthetase phenylalanine ammonia lyase 

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Copyright information

© Springer 2007

Authors and Affiliations

  • Łukasz Berlicki
    • 1
  • Jolanta Grembecka
    • 1
  • Edyta Dyguda-Kazimierowicz
    • 1
  • PaweŁ Kafarski
    • 1
  • W. Andrzej Sokalski
    • 1
  1. 1.Department of ChemistryWrocŃaw University of TechnologyWrocŃawPoland

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