The prospect for consistent computer-aided refinement of stereoselective enzymes is explored by simulating the hydrolysis of enantiomers of an a-substituted ester by wild-type and mutant Candida antarctica lipase A, using several strategies. In particular, we focused on the use of the empirical valence bond (EVB) method in a quantitative screening for enantioselectivity, and evaluate both kcat and kcat/KM of the R and S stereoisomers. We found that an extensive sampling is essential for obtaining converging results. This requirement points towards possible problems with approaches that use a limited conformational sampling. However, performing the proper sampling appears to give encouraging results and to offer a powerful tool for the computer-aided design of enantioselective enzymes. We also explore faster strategies for identifying mutations that will help in augmenting directed-evolution experiments, but these approaches require further refinement.