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

Lipase from Burkholderia cepacia (BCL, previously Pseudomonas cepacia) has proven to be useful biocatalyst for obtaining enantiomerically pure compounds, particularly secondary and primary alcohols and their esters. Previously we derived 3D Quantitative Structure Activity Relationships (QSARs) for predicting enantioselectivity of BCL towards 3-(aryloxy)-1, 2-propanediol derivatives. In this work we used these models to predict the stereoselectivity for a new set of diverse secondary alcohols. Despite significant differences of the data sets and the molecular modelling procedure utilised, stereoselectivity is predicted in agreement with the results of kinetic resolution. We combined the lipase-substrate complexes that we analysed earlier with those presented in this work, and derived a new model. Since derived for the chemically diverse set of secondary alcohols, this model is more general than those obtained previously for the twelve BCL- 3-(aryloxy)-1, 2-propanediols complexes and should be able to predict stereo-selectivity of BCL towards the wide range of secondary alcohols. This is demonstrated for two alpha-methylene-beta- hydroxy esters. Further more, 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 in this work, 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.

3D QSAR ; COMBINE ; lipase ; stereoselectivity

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