title: Linear Interaction Energy Based Prediction of Cytochrome P450 1A2 Binding Affinities with Reliability Estimation.
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).
authors.affiliation: AIMMS Division of Molecular Toxicology, Department of Chemistry and Pharmaceutical Sciences, VU University, De Boelelaan 1083, 1081 HV Amsterdam, The Netherlands.
authors.forename: Luigi
authors.initials: L
authors.lastname: Capoferri
authors.affiliation: AIMMS Division of Molecular Toxicology, Department of Chemistry and Pharmaceutical Sciences, VU University, De Boelelaan 1083, 1081 HV Amsterdam, The Netherlands.
authors.forename: Marlies C A
authors.initials: MC
authors.lastname: Verkade-Vreeker
authors.affiliation: AIMMS Division of Molecular Toxicology, Department of Chemistry and Pharmaceutical Sciences, VU University, De Boelelaan 1083, 1081 HV Amsterdam, The Netherlands.
authors.forename: Danny
authors.initials: D
authors.lastname: Buitenhuis
authors.affiliation: AIMMS Division of Molecular Toxicology, Department of Chemistry and Pharmaceutical Sciences, VU University, De Boelelaan 1083, 1081 HV Amsterdam, The Netherlands.
authors.forename: Jan N M
authors.initials: JN
authors.lastname: Commandeur
authors.affiliation: Research Programme on Biomedical Informatics (GRIB), Department of Experimental and Health Sciences, Universitat Pompeu Fabra, IMIM (Hospital del Mar Medical Research Institute), Dr. Aiguader, 88, E-08003 Barcelona, Spain.
authors.forename: Manuel
authors.initials: M
authors.lastname: Pastor
authors.affiliation: AIMMS Division of Molecular Toxicology, Department of Chemistry and Pharmaceutical Sciences, VU University, De Boelelaan 1083, 1081 HV Amsterdam, The Netherlands.
authors.forename: Nico P E
authors.initials: NP
authors.lastname: Vermeulen
authors.affiliation: AIMMS Division of Molecular Toxicology, Department of Chemistry and Pharmaceutical Sciences, VU University, De Boelelaan 1083, 1081 HV Amsterdam, The Netherlands.
authors.forename: Daan P
authors.initials: DP
authors.lastname: Geerke
mesh_terms: D020134:Catalytic Domain; D019388:Cytochrome P-450 CYP1A2 / Q000737:chemistry* / Q000378:metabolism*; D004347:Drug Interactions; D006801:Humans; D008024:Ligands; D056004:Molecular Dynamics Simulation; D011485:Protein Binding; D011487:Protein Conformation; D015203:Reproducibility of Results; D055672:Static Electricity; D013816:Thermodynamics
chemical_list: D008024:Ligands; C504573:CYP1A2 protein, human; D019388:Cytochrome P-450 CYP1A2