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Discriminant and quantitative PLS analysis of competitive CYP2C9 inhibitors versus non-inhibitors using alignment independent GRIND descriptors.
Uppsala universitet, Medicinska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för organisk farmaceutisk kemi.
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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
Ort, förlag, år, upplaga, sidor
2002. Vol. 16, s. 443 - 458
Identifikatorer
URN: urn:nbn:se:uu:diva-91426OAI: oai:DiVA.org:uu-91426DiVA, id: diva2:164148
Tillgänglig från: 2004-02-27 Skapad: 2004-02-27Bibliografiskt granskad
Ingår i avhandling
1. Computational Modelling of Structures and Ligands of CYP2C9
Öppna denna publikation i ny flik eller fönster >>Computational Modelling of Structures and Ligands of CYP2C9
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
Pharmaceutical chemistry, CYP2C9, 3D QSAR, GRID, CYP450, pharmacophore modelling, homology modelling, metabolism, competitive inhibitors, CPCA, molecular dynamics simulations, Farmaceutisk kemi
Nationell ämneskategori
Läkemedelskemi
Forskningsämne
läkemedelskemi
Identifikatorer
urn:nbn:se:uu:diva-4016 (URN)91-554-5891-2 (ISBN)
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

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