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Computational Modelling of Structures and Ligands of CYP2C9
Uppsala universitet, Medicinska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för organisk farmaceutisk kemi.
2004 (Engelska)Doktorsavhandling, sammanläggning (Övrigt vetenskapligt)
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.

Ort, förlag, år, upplaga, sidor
Uppsala: Acta Universitatis Upsaliensis , 2004. , s. 77
Serie
Comprehensive Summaries of Uppsala Dissertations from the Faculty of Pharmacy, ISSN 0282-7484 ; 311
Nyckelord [en]
Pharmaceutical chemistry, CYP2C9, 3D QSAR, GRID, CYP450, pharmacophore modelling, homology modelling, metabolism, competitive inhibitors, CPCA, molecular dynamics simulations
Nyckelord [sv]
Farmaceutisk kemi
Nationell ämneskategori
Läkemedelskemi
Forskningsämne
läkemedelskemi
Identifikatorer
URN: urn:nbn:se:uu:diva-4016ISBN: 91-554-5891-2 (tryckt)OAI: oai:DiVA.org:uu-4016DiVA, id: diva2:164153
Disputation
2004-03-25, B42, BMC, Uppsala Universitet, Uppsala, 13:15
Opponent
Handledare
Tillgänglig från: 2004-02-27 Skapad: 2004-02-27 Senast uppdaterad: 2018-01-13Bibliografiskt granskad
Delarbeten
1. Competitive CYP2C9 Inhibitors: Enzyme inhibition Studies, Protein Homology Modelling, and Three-Dimensional Quantitative Structure Activity Relationship Analysis
Öppna denna publikation i ny flik eller fönster >>Competitive CYP2C9 Inhibitors: Enzyme inhibition Studies, Protein Homology Modelling, and Three-Dimensional Quantitative Structure Activity Relationship Analysis
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2001 Ingår i: Molecular Pharmacology, ISSN 0026-895, Vol. 59, s. 909 - 919Artikel i tidskrift (Refereegranskat) Published
Identifikatorer
urn:nbn:se:uu:diva-91425 (URN)
Tillgänglig från: 2004-02-27 Skapad: 2004-02-27Bibliografiskt granskad
2. Discriminant and quantitative PLS analysis of competitive CYP2C9 inhibitors versus non-inhibitors using alignment independent GRIND descriptors.
Öppna denna publikation i ny flik eller fönster >>Discriminant and quantitative PLS analysis of competitive CYP2C9 inhibitors versus non-inhibitors using alignment independent GRIND descriptors.
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2002 Ingår i: Journal of Computer-Aided Molecular Design, ISSN 0920-654, Vol. 16, s. 443 - 458Artikel i tidskrift (Refereegranskat) Published
Identifikatorer
urn:nbn:se:uu:diva-91426 (URN)
Tillgänglig från: 2004-02-27 Skapad: 2004-02-27Bibliografiskt granskad
3. Predicting Drug Metabolism: A Site of Metabolism Tool Applied to the Cytochrome P450 CYP2C9.
Öppna denna publikation i ny flik eller fönster >>Predicting Drug Metabolism: A Site of Metabolism Tool Applied to the Cytochrome P450 CYP2C9.
2003 Ingår i: Journal of Medicinal Chemistry, ISSN 0022-2623, Vol. 46, nr 12, s. 2313-2324Artikel i tidskrift (Refereegranskat) Published
Identifikatorer
urn:nbn:se:uu:diva-91427 (URN)
Tillgänglig från: 2004-02-27 Skapad: 2004-02-27Bibliografiskt granskad
4. A Conformer and Alignment independent model to predict structurally diverse competitive CYP2C9 inhibitors.
Öppna denna publikation i ny flik eller fönster >>A Conformer and Alignment independent model to predict structurally diverse competitive CYP2C9 inhibitors.
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2004 Ingår i: Journal of Medicinal Chemistry, ISSN 0022-2623, Vol. Web Release Date: 13-JanArtikel i tidskrift (Refereegranskat) Published
Identifikatorer
urn:nbn:se:uu:diva-91428 (URN)
Tillgänglig från: 2004-02-27 Skapad: 2004-02-27Bibliografiskt granskad
5. Structural analysis of CYP2C9 and CYP2C5 and critical assessment of molecular modelling techniques.
Öppna denna publikation i ny flik eller fönster >>Structural analysis of CYP2C9 and CYP2C5 and critical assessment of molecular modelling techniques.
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Manuskript (Övrigt vetenskapligt)
Identifikatorer
urn:nbn:se:uu:diva-91429 (URN)
Tillgänglig från: 2004-02-27 Skapad: 2004-02-27 Senast uppdaterad: 2010-01-13Bibliografiskt granskad
6. Virtual receptor site (VRS) derivation for competitive CYP2C9 inhibitors: - a novel approach for structurally diverse compounds.
Öppna denna publikation i ny flik eller fönster >>Virtual receptor site (VRS) derivation for competitive CYP2C9 inhibitors: - a novel approach for structurally diverse compounds.
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Manuskript (Övrigt vetenskapligt)
Identifikatorer
urn:nbn:se:uu:diva-91430 (URN)
Tillgänglig från: 2004-02-27 Skapad: 2004-02-27 Senast uppdaterad: 2010-01-13Bibliografiskt granskad

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