Stereoselectivity of Burkholderia cepacia lipase towards secondary alcohols: molecular modelling and 3D QSAR approach

摘要

Lipase from Burkholderia cepacia (BCL, previously Pseudomonas cepacia) has proven to be a useful biocatalyst for obtaining enantiomerically pure compounds, in particular primary and secondary alcohols and their esters. Previously we derived 3D quantitative structure-activity relationships (QSARs) for predicting the enantioselectivity of BCL towards 3-(aryloxy)-1,2-propanediol derivatives. Herein we used these models to predict the stereo selectivity for a new set of diverse secondary alcohols. Despite significant differences in the data sets and the molecular modelling procedure utilised, the stereoselectivity was predicted in agreement with the results of kinetic resolution. We have combined the lipase-substrate complexes that we analysed earlier with those presented herein and derived a new model. Since this model is derived for the chemically diverse set of secondary alcohols, it is more general than those obtained previously for the 12 BCL-3-(aryloxy)-1,2-propanediols complexes and should be able to predict the stereoselectivity of BCL towards a wide range of secondary alcohols. This is demonstrated for two alpha-methylene-beta-hydroxy esters. Additionally, we modelled a mutant BCL and, using the COMparative BINding Energy (COMBINE) analysis, predicted its stereoselectivity towards a few randomly selected secondary alcohols. The Monte Carlo based conformational search, used herein, turned out to be faster and more convenient for investigating the binding modes of secondary alcohols in the BCL active site than the systematic search used in our previous work. (C) 2004 Elsevier Ltd. All rights reserved.