Structure-based estimation of enzymatic hydrolysis rates and its application in computer-aided retrometabolic drug design

After a brief review of the problems related to the description of enzymati c hydrolysis rates and the quantification of steric effects, a recently dev eloped method that uses the inaccessible solid angle Omega h calculated aro und different atoms as a novel steric parameter to estimate human blood in vitro enzymatic hydrolysis rates in noncongener ester series is summarized. Some illustrative results obtained by the integration of this method into the expert system developed for computer-aided soft drug design are also pr esented. Starting from a lead compound, the system can provide full librari es of possible new "soft" molecular structures, a ranking order of these ca ndidates based on isosteric-isoelectronic analogy to the lead. and estimate d hydrolytic half-lives for all structures of interest.