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Computational Modelling of Structures and Ligands of CYP2C9
Uppsala University, Medicinska vetenskapsområdet, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
2004 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

CYP2C9 is one of our major drug metabolising enzymes and belongs to the cytochrome P450 (CYP) super family. The aim of this thesis was to gain an understanding of the quantitative structure–activity relationships (QSAR) of CYP2C9 substrates and inhibitors. This information will be useful in predicting drug metabolism and the potential for drug–drug interactions. To achieve this, a well characterised data set of structurally diverse, competitive CYP2C9 inhibitors was identified in our laboratory. Several computational methodologies, many based on GRID molecular interaction fields, were applied or developed in order to handle issues such as compound alignment and bioactive conformer selection. First, a traditional 3D QSAR was carried out in GOLPE, generating a predictive model. In this model the selection of a bioactive conformer and alignment was based on docking in a homology model of CYP2C9. Secondly, we introduced the concept of alignment independent descriptors from ALMOND. These descriptors were used to generate quantitatively and qualitatively predictive models. We subsequently derived conformation independent descriptors from molecular interaction fields calculated in FlexGRID. This enabled the derivation of 3D QSAR models without taking into account the selection of an alignment or a bioactive conformer. A subsequent programming effort enabled the conversion of this model back to 3D aligned pharmacophores. Similar alignment independent descriptors were also used in the development of the software MetaSite® that predicts the site of metabolism for CYP2C9 ligands. Finally, as crystal information on this isoform emerged, the performance of molecular dynamics simulations and homology models and the flexibility of the protein were evaluated using statistical analyses.

These modelling efforts have resulted in detailed knowledge of the structural characteristics in ligand interactions with the cytochrome P450 2C9 isoform.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis , 2004. , p. 77
Series
Comprehensive Summaries of Uppsala Dissertations from the Faculty of Pharmacy, ISSN 0282-7484 ; 311
Keywords [en]
Pharmaceutical chemistry, CYP2C9, 3D QSAR, GRID, CYP450, pharmacophore modelling, homology modelling, metabolism, competitive inhibitors, CPCA, molecular dynamics simulations
Keywords [sv]
Farmaceutisk kemi
National Category
Medicinal Chemistry
Research subject
Medicinal Chemistry
Identifiers
URN: urn:nbn:se:uu:diva-4016ISBN: 91-554-5891-2 (print)OAI: oai:DiVA.org:uu-4016DiVA, id: diva2:164153
Public defence
2004-03-25, B42, BMC, Uppsala Universitet, Uppsala, 13:15
Opponent
Supervisors
Available from: 2004-02-27 Created: 2004-02-27 Last updated: 2018-01-13Bibliographically approved
List of papers
1. Competitive CYP2C9 Inhibitors: Enzyme inhibition Studies, Protein Homology Modelling, and Three-Dimensional Quantitative Structure Activity Relationship Analysis
Open this publication in new window or tab >>Competitive CYP2C9 Inhibitors: Enzyme inhibition Studies, Protein Homology Modelling, and Three-Dimensional Quantitative Structure Activity Relationship Analysis
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2001 In: Molecular Pharmacology, ISSN 0026-895, Vol. 59, p. 909 - 919Article in journal (Refereed) Published
Identifiers
urn:nbn:se:uu:diva-91425 (URN)
Available from: 2004-02-27 Created: 2004-02-27Bibliographically approved
2. Discriminant and quantitative PLS analysis of competitive CYP2C9 inhibitors versus non-inhibitors using alignment independent GRIND descriptors.
Open this publication in new window or tab >>Discriminant and quantitative PLS analysis of competitive CYP2C9 inhibitors versus non-inhibitors using alignment independent GRIND descriptors.
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2002 In: Journal of Computer-Aided Molecular Design, ISSN 0920-654, Vol. 16, p. 443 - 458Article in journal (Refereed) Published
Identifiers
urn:nbn:se:uu:diva-91426 (URN)
Available from: 2004-02-27 Created: 2004-02-27Bibliographically approved
3. Predicting Drug Metabolism: A Site of Metabolism Tool Applied to the Cytochrome P450 CYP2C9.
Open this publication in new window or tab >>Predicting Drug Metabolism: A Site of Metabolism Tool Applied to the Cytochrome P450 CYP2C9.
2003 In: Journal of Medicinal Chemistry, ISSN 0022-2623, Vol. 46, no 12, p. 2313-2324Article in journal (Refereed) Published
Identifiers
urn:nbn:se:uu:diva-91427 (URN)
Available from: 2004-02-27 Created: 2004-02-27Bibliographically approved
4. A Conformer and Alignment independent model to predict structurally diverse competitive CYP2C9 inhibitors.
Open this publication in new window or tab >>A Conformer and Alignment independent model to predict structurally diverse competitive CYP2C9 inhibitors.
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2004 In: Journal of Medicinal Chemistry, ISSN 0022-2623, Vol. Web Release Date: 13-JanArticle in journal (Refereed) Published
Identifiers
urn:nbn:se:uu:diva-91428 (URN)
Available from: 2004-02-27 Created: 2004-02-27Bibliographically approved
5. Structural analysis of CYP2C9 and CYP2C5 and critical assessment of molecular modelling techniques.
Open this publication in new window or tab >>Structural analysis of CYP2C9 and CYP2C5 and critical assessment of molecular modelling techniques.
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Manuscript (Other academic)
Identifiers
urn:nbn:se:uu:diva-91429 (URN)
Available from: 2004-02-27 Created: 2004-02-27 Last updated: 2010-01-13Bibliographically approved
6. Virtual receptor site (VRS) derivation for competitive CYP2C9 inhibitors: - a novel approach for structurally diverse compounds.
Open this publication in new window or tab >>Virtual receptor site (VRS) derivation for competitive CYP2C9 inhibitors: - a novel approach for structurally diverse compounds.
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Manuscript (Other academic)
Identifiers
urn:nbn:se:uu:diva-91430 (URN)
Available from: 2004-02-27 Created: 2004-02-27 Last updated: 2010-01-13Bibliographically approved

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