Computer-aided techniques of rational design of enzyme inhibitors were reviewed.
lead generation and optimization protocols were outlined and several methods of inhibitor potency estimation by both empirical scoring functions as well as
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
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