Malleability and Versatility of Cytochrome P450 Active Sites
Studied by Molecular Simulations

J 2012

Malleability and Versatility of Cytochrome P450 Active Sites Studied by Molecular Simulations

OOSTENBRINK, Chris, Anita DE RUITER, Jozef HRITZ and Nico VERMEULEN

Basic information

Original name

Malleability and Versatility of Cytochrome P450 Active Sites Studied by Molecular Simulations

Authors

OOSTENBRINK, Chris, Anita DE RUITER, Jozef HRITZ and Nico VERMEULEN

Edition

CURRENT DRUG METABOLISM, SHARJAH, BENTHAM SCIENCE PUBL LTD, 2012, 1389-2002

Other information

Language

English

Type of outcome

Článek v odborném periodiku

Field of Study

Genetics and molecular biology

Country of publisher

United Arab Emirates

Confidentiality degree

není předmětem státního či obchodního tajemství

Impact factor

Impact factor: 4.405

Organization unit

Central European Institute of Technology

UT WoS

000300417500007

Keywords in English

Site of metabolism prediction; protein flexibility; molecular docking; molecular dynamics simulations; replica exchange

Abstract

V originále

As the most important phase I drug metabolizing enzymes, the human Cytochromes P450 display an enormous versatility in the molecular structures of possible substrates. Individual isoforms may preferentially bind specific classes of molecules, but also within these classes, some isoforms show remarkable levels of promiscuity. In this work, we try to link this promiscuity to the versatility and malleability of the active site at the hand of examples from our own work. Mainly focusing on the flexibility of protein structures and the presence or absence of water molecules, we establish molecular reasons for observed promiscuity, determine the relevant factors to take into account when predicting binding poses and rationalize the role of individual interactions in the process of ligand binding. A high level of active site flexibility does not only allow for the binding of a large variety of substrates and inhibitors, but also appears to be important to facilitate ligand binding and unbinding.

Citovat

OOSTENBRINK, Chris, Anita DE RUITER, Jozef HRITZ and Nico VERMEULEN. Malleability and Versatility of Cytochrome P450 Active Sites Studied by Molecular Simulations. CURRENT DRUG METABOLISM. SHARJAH: BENTHAM SCIENCE PUBL LTD, 2012, vol. 13, No 2, p. 190-196. ISSN 1389-2002.

@article{1166981,
   author = {Oostenbrink, Chris and de Ruiter, Anita and Hritz, Jozef and Vermeulen, Nico},
   article_location = {SHARJAH},
   article_number = {2},
   keywords = {Site of metabolism prediction; protein flexibility; molecular docking; molecular dynamics simulations; replica exchange},
   language = {eng},
   issn = {1389-2002},
   journal = {CURRENT DRUG METABOLISM},
   title = {Malleability and Versatility of Cytochrome P450 Active Sites Studied by Molecular Simulations},
   volume = {13},
   year = {2012}
}

TY  - JOUR
ID  - 1166981
AU  - Oostenbrink, Chris - de Ruiter, Anita - Hritz, Jozef - Vermeulen, Nico
PY  - 2012
TI  - Malleability and Versatility of Cytochrome P450 Active Sites Studied by Molecular Simulations
JF  - CURRENT DRUG METABOLISM
VL  - 13
IS  - 2
SP  - 190-196
EP  - 190-196
PB  - BENTHAM SCIENCE PUBL LTD
SN  - 13892002
KW  - Site of metabolism prediction
KW  - protein flexibility
KW  - molecular docking
KW  - molecular dynamics simulations
KW  - replica exchange
N2  - As the most important phase I drug metabolizing enzymes, the human Cytochromes P450 display an enormous versatility in the molecular structures of possible substrates. Individual isoforms may preferentially bind specific classes of molecules, but also within these classes, some isoforms show remarkable levels of promiscuity. In this work, we try to link this promiscuity to the versatility and malleability of the active site at the hand of examples from our own work. Mainly focusing on the flexibility of protein structures and the presence or absence of water molecules, we establish molecular reasons for observed promiscuity, determine the relevant factors to take into account when predicting binding poses and rationalize the role of individual interactions in the process of ligand binding. A high level of active site flexibility does not only allow for the binding of a large variety of substrates and inhibitors, but also appears to be important to facilitate ligand binding and unbinding.
ER  -

OOSTENBRINK, Chris, Anita DE RUITER, Jozef HRITZ and Nico VERMEULEN. Malleability and Versatility of Cytochrome P450 Active Sites Studied by Molecular Simulations. \textit{CURRENT DRUG METABOLISM}. SHARJAH: BENTHAM SCIENCE PUBL LTD, 2012, vol.~13, No~2, p.~190-196. ISSN~1389-2002.

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