title: QSAR Modelling of CYP3A4 Inhibition as a Screening Tool in the Context of DrugDrug Interaction Studies.
abstract: Drugdrug interaction potential (DDI), especially cytochrome P450 (CYP) 3A4 inhibition potential, is one of the most important parameters to be optimized before preclinical and clinical pharmaceutical development as regard to the number of marketed drug metabolized mainly by this CYP and potentially co-administered with the future drug. The present study aims to develop in silico models for CYP3A4 inhibition prediction to help medicinal chemists during the discovery phase and even before the synthesis of new chemical entities (NCEs), focusing on NCEs devoid of any inhibitory potential toward this CYP. In order to find a relevant relationship between CYP3A4 inhibition and chemical features of the screened compounds, we applied a genetic-algorithm-based QSAR exploratory tool SQS (Stochastic QSAR Sampler) in combination with different description approaches comprising alignment-independent Volsurf descriptors, ISIDA fragments and Topological Fuzzy Pharmacophore Triplets. The experimental data used to build models were extracted from an in-house database. We derived a model with good prediction ability that was confirmed on both newly synthesized compound and public dataset retrieved from Pubchem database. This model is a promising efficient tool for filtering out potentially problematic compounds.
authors.affiliation: Technologie Servier, 25-27 rue Eugène Vignat, 45000 Orléans, France.
authors.forename: Véronique
authors.initials: V
authors.lastname: Hamon
authors.affiliation: Laboratoire d'Infochimie, UMR 7177, CNRS-Université Louis Pasteur, Strasbourg, France.
authors.forename: Dragos
authors.initials: D
authors.lastname: Horvath
authors.affiliation: Laboratoire d'Infochimie, UMR 7177, CNRS-Université Louis Pasteur, Strasbourg, France.
authors.forename: Cédric
authors.initials: C
authors.lastname: Gaudin
authors.affiliation: Technologie Servier, 25-27 rue Eugène Vignat, 45000 Orléans, France.
authors.forename: Julie
authors.initials: J
authors.lastname: Desrivot
authors.affiliation: Technologie Servier, 25-27 rue Eugène Vignat, 45000 Orléans, France.
authors.forename: Céline
authors.initials: C
authors.lastname: Junges
authors.affiliation: Technologie Servier, 25-27 rue Eugène Vignat, 45000 Orléans, France.
authors.forename: Alban
authors.initials: A
authors.lastname: Arrault
authors.affiliation: Technologie Servier, 25-27 rue Eugène Vignat, 45000 Orléans, France.
authors.forename: Marc
authors.initials: M
authors.lastname: Bertrand
authors.affiliation: Technologie Servier, 25-27 rue Eugène Vignat, 45000 Orléans, France. philippe.vayer@fr.netgrs.com.
authors.forename: Philippe
authors.initials: P
authors.lastname: Vayer
keywords: ADME-Tox; Cytochrome P450 3A4; Drug discovery; High throughput screening; Inhibition