Rational mutagenesis of pig liver esterase (PLE-1) to resolve racemic clopidogrel
Gaber, Yasser LU ; Ismail, Mohamed LU
; Bisagni, Serena
LU
; Takwa, Mohamad
LU
and Hatti-Kaul, Rajni
LU
(2015)
In Journal of Molecular Catalysis B: Enzymatic
122.
p.156-162
- Abstract
- Clopidogrel is an important and widely used antiplatelet drug; only the (S)-isomer is the active biological enantiomer. The industrial production of the active enantiomer involves resolution of the racemic compound using stoichiometric amounts of L-camphor sulphonic acid and crystallization in a process using large amounts of solvent. In the present study, the possibility of enzyme catalysed kinetic resolution was investigated. Screening of a number of hydrolytic enzymes showed the crude pig liver esterase (PLE) to exhibit modest enantioselectivity in the hydrolysis of racemic clopidogrel. Molecular modeling simulations were applied on the homology model of PLE-1, the major isoenzyme in the crude PLE, and distinct sites of mutations were... (More)
- Clopidogrel is an important and widely used antiplatelet drug; only the (S)-isomer is the active biological enantiomer. The industrial production of the active enantiomer involves resolution of the racemic compound using stoichiometric amounts of L-camphor sulphonic acid and crystallization in a process using large amounts of solvent. In the present study, the possibility of enzyme catalysed kinetic resolution was investigated. Screening of a number of hydrolytic enzymes showed the crude pig liver esterase (PLE) to exhibit modest enantioselectivity in the hydrolysis of racemic clopidogrel. Molecular modeling simulations were applied on the homology model of PLE-1, the major isoenzyme in the crude PLE, and distinct sites of mutations were proposed and 'produced in the laboratory. The PLE-1 variants with one mutation i.e. PLE-1-F407L and PLE-1-F407I resolved the racemic substrate yielding the (R)-isomer with E value >100. Contrarily, the isoenzyme PLE-3 resolved the racemic substrate yielding (S)-clopidogrel with E value of 10. (C) 2015 Elsevier B.V. All rights reserved. (Less)
Please use this url to cite or link to this publication:
https://lup.lub.lu.se/record/8557009
- author
- Gaber, Yasser
LU
; Ismail, Mohamed
LU
; Bisagni, Serena
LU
; Takwa, Mohamad
LU
and Hatti-Kaul, Rajni
LU
- organization
- publishing date
- 2015
- type
- Contribution to journal
- publication status
- published
- subject
- keywords
- Clopidogrel, Kinetic resolution, Molecular modeling, Enantioselectivity, Esterase
- in
- Journal of Molecular Catalysis B: Enzymatic
- volume
- 122
- pages
- 7 pages
- publisher
- Elsevier
- external identifiers
-
- wos:000366078800019
- scopus:84942755601
- ISSN
- 1873-3158
- DOI
- 10.1016/j.molcatb.2015.09.001
- language
- English
- LU publication?
- yes
- id
- f56b4bf1-29b8-4c6b-926e-6cc541db873f (old id 8557009)
- date added to LUP
- 2016-04-01 10:47:42
- date last changed
- 2023-08-25 13:53:24
@article{f56b4bf1-29b8-4c6b-926e-6cc541db873f,
abstract = {{Clopidogrel is an important and widely used antiplatelet drug; only the (S)-isomer is the active biological enantiomer. The industrial production of the active enantiomer involves resolution of the racemic compound using stoichiometric amounts of L-camphor sulphonic acid and crystallization in a process using large amounts of solvent. In the present study, the possibility of enzyme catalysed kinetic resolution was investigated. Screening of a number of hydrolytic enzymes showed the crude pig liver esterase (PLE) to exhibit modest enantioselectivity in the hydrolysis of racemic clopidogrel. Molecular modeling simulations were applied on the homology model of PLE-1, the major isoenzyme in the crude PLE, and distinct sites of mutations were proposed and 'produced in the laboratory. The PLE-1 variants with one mutation i.e. PLE-1-F407L and PLE-1-F407I resolved the racemic substrate yielding the (R)-isomer with E value >100. Contrarily, the isoenzyme PLE-3 resolved the racemic substrate yielding (S)-clopidogrel with E value of 10. (C) 2015 Elsevier B.V. All rights reserved.}},
author = {{Gaber, Yasser and Ismail, Mohamed and Bisagni, Serena and Takwa, Mohamad and Hatti-Kaul, Rajni}},
issn = {{1873-3158}},
keywords = {{Clopidogrel; Kinetic resolution; Molecular modeling; Enantioselectivity; Esterase}},
language = {{eng}},
pages = {{156--162}},
publisher = {{Elsevier}},
series = {{Journal of Molecular Catalysis B: Enzymatic}},
title = {{Rational mutagenesis of pig liver esterase (PLE-1) to resolve racemic clopidogrel}},
url = {{http://dx.doi.org/10.1016/j.molcatb.2015.09.001}},
doi = {{10.1016/j.molcatb.2015.09.001}},
volume = {{122}},
year = {{2015}},
}