Structural and energetic determinants for enantiopreferences in kinetic resolution of lipases

Bocola, Marco; Stubbs, Milton T.; Sotriffer, Christoph A.; Hauer, Bernhard; Friedrich, Thomas; Dittrich, K.-H.; Klebe, G.

doi:10.1093/protein/gzg047

Cited by 35 publications

(14 citation statements)

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“…64 A similar, quite recent, study of the resolution of 2a by CaLB indicated that the hydrogen atom and the methyl group at C-1 exchange their positions. 65 It would seem that the mechanistic explanation of lipase enantioselectivity is a good deal more complex and interesting than expected.…”

Section: Lipases: Enantiorecognition Revisitedmentioning

confidence: 99%

Enantioselective acylation of chiral amines catalysed by serine hydrolases

2004

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Section: Lipases: Enantiorecognition Revisitedmentioning

confidence: 99%

Enantioselective acylation of chiral amines catalysed by serine hydrolases

2004

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“…This loss in mobility corresponds to a loss in binding entropy. In a recent study we could demonstrate experimentally that this loss in molecular motion is an important determinant in descriminating the turnover rate of stereoisomers in chiral resolution [33]. Since rigid molecules will experience a smaller conformational space and will accordingly suffer from smaller entropic losses upon immobilization in a binding pocket, the affinity will scale to some extent with the number of rotatable bonds.…”

Section: A First Attempt: Virtual Screening Focussed On the Most Prommentioning

confidence: 99%

Strategies for the design of inhibitors of aldose reductase, an enzyme showing pronounced induced-fit adaptations

Klebe

Krämer

Sotriffer

2004

Cellular and Molecular Life Sciences (CMLS)

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Aldose reductase is involved in the polyol pathway, catalyzing the reduction of glucose to sorbitol. However, due to pronounced binding site adaptations, the enzyme can operate on a broad palette of structurally diverse substrates ranging from small aliphatic and aromatic aldehydes up to steroid-type ligands. A comparative analysis of the presently accessible crystal structures of aldose reductase complexes reveals four binding-competent protein conformations. Additional relevant conformers are detected through molecular dynamics simulations. They indicate an equilibrium of several conformers which is shifted towards the binding-competent geometries upon ligand binding. Such a manifold system with several alternative binding site conformers requires some tailored concepts in virtual screening. We followed two strategies, both successfully suggesting new micromolar inhibitors. In a first attempt, we concentrated on one preferred conformer and performed a virtual screening, assuming that the binding pocket of aldose reductase adopts only this conformation. In a second approach, we followed a ligand superpositioning method. Ligands were extracted in their bound conformations from three different crystal structures, all accommodating the ligands with different active site conformations. After merging these ligands into one supermolecule, mutual alignments were computed, taking candidate ligands from a screening database. The latter strategy also retrieved several structurally new inhibitors of micromolar potency.

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“…This tight binding of substrates to enzyme can lead to a drastic decline in system entropy. Usually, the enzyme that presents higher enantioselectivity has the preferred substrate enantiomer bound in tighter way, thus, results in bigger entropy lose (Bocola et al, 2003). It has been revealed that the entropy difference between enantiomers (DDS 6 ¼ ) has enormous contribution to the reaction DDG 6 ¼ value (Ottosson et al, 2001(Ottosson et al, , 2002Overbeeke et al, 1998).…”

Section: Prediction Errormentioning

confidence: 99%

Prediction of the enantioselectivity of lipases and esterases by molecular docking method with modified force field parameters

Ji¹,

Tang²,

Yu³

2009

Biotech & Bioengineering

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In the work, molecular docking method was applied to extensively predict the enantioselectivity of lipases and esterases. A ligand library consisted of 69 chiral substrates was docked to four lipases and two esterases to set up the prediction model. During the docking process, necessary modification was carried out on van de Waals and hydrogen bond parameters of enzyme/substrate pair so that the ligands were able to adopt productive geometry in the enzymes. The docking results correctly indicated the enantiopreference for 91% (63/69) of docking pairs and the docking energy difference between substrate enantiomers (Delta Delta G(docking)) was significantly (correlation coefficient = 0.72, P < 0.05) correlated with the activation free energy difference (Delta Delta G( not equal)) that was quantitatively correlated with enantioselectivity of the enzymes. The prediction method was further validated by docking with another 12 enzyme/substrate pairs. Moreover, the prediction error was susceptible to the size of groups bonded to substrate's chiral center and expected Delta Delta G( not equal) values but was not related to the substrate type and reaction medium. The possible reasons of observed error were discussed. It is demonstrated that the docking method has great application potential in high performance prediction of enzyme enantioselectivity.

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Structural and energetic determinants for enantiopreferences in kinetic resolution of lipases

Cited by 35 publications

References 1 publication

Enantioselective acylation of chiral amines catalysed by serine hydrolases

Enantioselective acylation of chiral amines catalysed by serine hydrolases

Strategies for the design of inhibitors of aldose reductase, an enzyme showing pronounced induced-fit adaptations

Prediction of the enantioselectivity of lipases and esterases by molecular docking method with modified force field parameters

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