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A Conformer and Alignment independent model to predict structurally diverse competitive CYP2C9 inhibitors.
Uppsala universitet, Medicinska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för organisk farmaceutisk kemi.
Vise andre og tillknytning
2004 Inngår i: Journal of Medicinal Chemistry, ISSN 0022-2623, Vol. Web Release Date: 13-JanArtikkel i tidsskrift (Fagfellevurdert) Published
sted, utgiver, år, opplag, sider
2004. Vol. Web Release Date: 13-Jan
Identifikatorer
URN: urn:nbn:se:uu:diva-91428OAI: oai:DiVA.org:uu-91428DiVA, id: diva2:164150
Tilgjengelig fra: 2004-02-27 Laget: 2004-02-27bibliografisk kontrollert
Inngår i avhandling
1. Computational Modelling of Structures and Ligands of CYP2C9
Åpne denne publikasjonen i ny fane eller vindu >>Computational Modelling of Structures and Ligands of CYP2C9
2004 (engelsk)Doktoravhandling, med artikler (Annet vitenskapelig)
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.

sted, utgiver, år, opplag, sider
Uppsala: Acta Universitatis Upsaliensis, 2004. s. 77
Serie
Comprehensive Summaries of Uppsala Dissertations from the Faculty of Pharmacy, ISSN 0282-7484 ; 311
Emneord
Pharmaceutical chemistry, CYP2C9, 3D QSAR, GRID, CYP450, pharmacophore modelling, homology modelling, metabolism, competitive inhibitors, CPCA, molecular dynamics simulations, Farmaceutisk kemi
HSV kategori
Forskningsprogram
läkemedelskemi
Identifikatorer
urn:nbn:se:uu:diva-4016 (URN)91-554-5891-2 (ISBN)
Disputas
2004-03-25, B42, BMC, Uppsala Universitet, Uppsala, 13:15
Opponent
Veileder
Tilgjengelig fra: 2004-02-27 Laget: 2004-02-27 Sist oppdatert: 2018-01-13bibliografisk kontrollert

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