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Rational mutagenesis of pig liver esterase (PLE-1) to resolve racemic clopidogrel

Gaber, Yasser LU ; Ismail, Mohamed; 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)
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author
organization
publishing date
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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
156 - 162
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
2016-01-25 09:03:51
date last changed
2017-01-01 03:54:08
@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},
  keyword      = {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},
  volume       = {122},
  year         = {2015},
}