Linear interaction energy based prediction of cytochrome P450 1A2 binding affinities with reliability estimation.
Mostra el registre complet Registre parcial de l'ítem
- dc.contributor.author Capoferri, Luigica
- dc.contributor.author Verkade-Vreeker, Marlies C. A.ca
- dc.contributor.author Buitenhuis, Dannyca
- dc.contributor.author Commandeu, Jan N.M.ca
- dc.contributor.author Pastor Maeso, Manuelca
- dc.contributor.author Vermeulen, Nico P. E.ca
- dc.contributor.author Geerke, Daan P.ca
- dc.date.accessioned 2016-01-18T09:04:58Z
- dc.date.available 2016-01-18T09:04:58Z
- dc.date.issued 2015
- 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).ca
- 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/pdfca
- 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.ca
- dc.identifier.doi http://dx.doi.org/10.1371/journal.pone.0142232
- dc.identifier.issn 1932-6203
- dc.identifier.uri http://hdl.handle.net/10230/25588
- dc.language.iso engca
- dc.publisher Public Library of Scienceca
- dc.relation.ispartof PLoS ONE. 2015 Nov 9;10(11):e0142232
- dc.relation.projectID info:eu-repo/grantAgreement/EC/FP7/115002
- 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.ca
- dc.rights.accessRights info:eu-repo/semantics/openAccessca
- dc.rights.uri http://creativecommons.org/licenses/by/4.0/ca
- dc.subject.other Citocrom P-450 -- Metabolismeca
- dc.title Linear interaction energy based prediction of cytochrome P450 1A2 binding affinities with reliability estimation.ca
- dc.type info:eu-repo/semantics/articleca
- dc.type.version info:eu-repo/semantics/publishedVersionca