engleski

Towards understanding enentio-selective enzyme catalysed chemical transformation of pro-drugs

Mirror-image versions (enantiomers) of chiral molecules are not structurally identical, and while one enantiomer is acting as a drug, the other may be inactive or even severely harmful. That is why it is important that drugs are enantio-selectively clear. However, production of only one enatiomer in a chemical reaction is often a problem. Bacterial lipases are interesting for biotechnology because of their high enantioselectivity toward chemically and pharmaceutically important compounds. Lipase from bacteria Burkholderia cepacia (BCL) catalyzes esterification of both primary and secondary alcohols with good enantioselectivity producing compounds which are important building blocks for many chiral drugs. Herein we report study of the reaction pathway for BCL using density functional theory based quantum mechanics-molecular mechanics modeling (QM/MM). The reaction was accomplished for two enantiomers of 1-phenoxy-2-hydroxybutane (1), which binding modes were determined previously by molecular dynamics and Monte Carlo conformational search1. The experimentally determined enantiomeric ratio and the calculated one, E=e(-??G/RT) are of the same order of magnitude when the free energy difference, ??G is approximated with the QM/MM energy difference between the modelled hydrated BCL - S-E1 and the BCL - R-E1 tetrahedral complexes. References: 1. Tomič S., Bertoša B., Kojić-Prodić B. and Kolosvary I. Tetrahedron: Asymmetry 15 (2004), 1163-1172.

lipase; reactions; enantioselectivity; QM/MM

nije evidentirano