Welcome to the UPF Digital Repository

Linear interaction energy based prediction of cytochrome P450 1A2 binding affinities with reliability estimation.

Show simple item record

dc.contributor.author Capoferri, Luigi
dc.contributor.author Verkade-Vreeker, Marlies C. A.
dc.contributor.author Buitenhuis, Danny
dc.contributor.author Commandeu, Jan N.M.
dc.contributor.author Pastor Maeso, Manuel
dc.contributor.author Vermeulen, Nico P. E.
dc.contributor.author Geerke, Daan P.
dc.date.accessioned 2016-01-18T09:04:58Z
dc.date.available 2016-01-18T09:04:58Z
dc.date.issued 2015
dc.identifier.citation Capoferri L, Verkade-Vreeker MC, Buitenhuis D, Commandeur JN, Pastor M, Vermeulen NP. et al. Linear interaction energy based prediction of cytochrome P450 1A2 binding affinities with reliability estimation. PLoS One. 2015 Nov 9;10(11):e0142232. doi: 10.1371/journal.pone.0142232.
dc.identifier.issn 1932-6203
dc.identifier.uri http://hdl.handle.net/10230/25588
dc.description.abstract Prediction of human Cytochrome P450 (CYP) binding affinities of small ligands, i.e., substrates and inhibitors, represents an important task for predicting drug-drug interactions. A quantitative assessment of the ligand binding affinity towards different CYPs can provide an estimate of inhibitory activity or an indication of isoforms prone to interact with the substrate of inhibitors. However, the accuracy of global quantitative models for CYP substrate binding or inhibition based on traditional molecular descriptors can be limited, because of the lack of information on the structure and flexibility of the catalytic site of CYPs. Here we describe the application of a method that combines protein-ligand docking, Molecular Dynamics (MD) simulations and Linear Interaction Energy (LIE) theory, to allow for quantitative CYP affinity prediction. Using this combined approach, a LIE model for human CYP 1A2 was developed and evaluated, based on a structurally diverse dataset for which the estimated experimental uncertainty was 3.3 kJ mol-1. For the computed CYP 1A2 binding affinities, the model showed a root mean square error (RMSE) of 4.1 kJ mol-1 and a standard error in prediction (SDEP) in cross-validation of 4.3 kJ mol-1. A novel approach that includes information on both structural ligand description and protein-ligand interaction was developed for estimating the reliability of predictions, and was able to identify compounds from an external test set with a SDEP for the predicted affinities of 4.6 kJ mol-1 (corresponding to 0.8 pKi units).
dc.description.sponsorship The work was supported by Innovative Medicines Initiative Joint Undertaking (IMI-JU) under grant agreement no. 115002 (eTOX), resources of which are composed of financial contribution from the European Union Seventh Framework Programme/n(FP7/20072013) and EFPIA companies in kind contribution; www.etoxproject.eu. The work was also supported by The Netherlands Organisation for Scientific Research (NWO, VIDI grant 723.012.105); www.nwo.nl.
dc.format.mimetype application/pdf
dc.language.iso eng
dc.publisher Public Library of Science
dc.rights © 2015 Capoferri et al. This is an open access article distributed under the terms of the http://creativecommons.org/licenses/by/4.0/, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
dc.rights.uri http://creativecommons.org/licenses/by/4.0/
dc.subject.other Citocrom P-450 -- Metabolisme
dc.title Linear interaction energy based prediction of cytochrome P450 1A2 binding affinities with reliability estimation.
dc.type info:eu-repo/semantics/article
dc.identifier.doi http://dx.doi.org/10.1371/journal.pone.0142232
dc.relation.projectID info:eu-repo/grantAgreement/EC/FP7/115002
dc.rights.accessRights info:eu-repo/semantics/openAccess
dc.type.version info:eu-repo/semantics/publishedVersion


This item appears in the following Collection(s)

Show simple item record

Search DSpace


Advanced Search

Browse

My Account

Statistics

Compliant to Partaking