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

After a brief review of the problems related to the description of enzymatic hydrolysis rates and the quantification of steric effects, a recently developed method that uses the inaccessible solid angle omega h calculated around 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 presented. Starting from a lead compound, the system can provide full libraries of possible new "soft" molecular structures, a ranking order of these candidates based on isosteric-isoelectronic analogy to the lead, and estimated hydrolytic half-lives for all structures of interest.