A Fragment-Based Approach for the Computational Prediction of the Nonspecific Binding of Drugs to Hepatic Microsomes
Open Access
- 19 August 2016
- journal article
- research article
- Published by American Society for Pharmacology & Experimental Therapeutics (ASPET) in Drug Metabolism and Disposition
- Vol. 44 (11), 1794-1798
- https://doi.org/10.1124/dmd.116.071852
Abstract
Correction for the nonspecific binding (NSB) of drugs to liver microsomes is essential for the accurate measurement of the kinetic parameters Km and Ki, and hence in vitro–in vivo extrapolation to predict hepatic clearance and drug–drug interaction potential. Although a number of computational approaches for the estimation of drug microsomal NSB have been published, they generally rely on compound lipophilicity and charge state at the expense of other physicochemical and chemical properties. In this work, we report the development of a fragment-based hologram quantitative structure activity relationship (HQSAR) approach for the prediction of NSB using a database of 132 compounds. The model has excellent predictivity, with a noncross-validated r2 of 0.966 and cross-validated r2 of 0.680, with a predictive r2 of 0.748 for an external test set comprising 34 drugs. The HQSAR method reliably predicted the fraction unbound in incubations of 95% of the training and test set drugs, excluding compounds with a steroid or morphinan 4,5-epoxide nucleus. Using the same data set of compounds, performance of the HQSAR method was superior to a model based on logP/D as the sole descriptor (predictive r2 for the test set compounds, 0.534). Thus, the HQSAR method provides an alternative approach to laboratory-based procedures for the prediction of the NSB of drugs to liver microsomes, irrespective of the drug charge state (acid, base, or neutral).This publication has 32 references indexed in Scilit:
- The Nonspecific Binding of Tyrosine Kinase Inhibitors to Human Liver MicrosomesDrug Metabolism and Disposition, 2015
- Structure-Based Prediction of the Nonspecific Binding of Drugs to Hepatic MicrosomesThe AAPS Journal, 2009
- In Silico Modeling of Nonspecific Binding to Human Liver MicrosomesDrug Metabolism and Disposition, 2008
- Hepatocellular Binding of Drugs: Correction for Unbound Fraction in Hepatocyte Incubations Using Microsomal Binding or Drug Lipophilicity DataDrug Metabolism and Disposition, 2008
- Drug Lipophilicity and Microsomal Protein Concentration as Determinants in the Prediction of the Fraction Unbound in Microsomal IncubationsDrug Metabolism and Disposition, 2007
- The Impact of In Vitro Binding on In Vitro - In Vivo Extrapolations, Projections of Metabolic Clearance and Clinical Drug-Drug InteractionsCurrent Drug Metabolism, 2006
- BINDING OF DRUGS TO HEPATIC MICROSOMES: COMMENT AND ASSESSMENT OF CURRENT PREDICTION METHODOLOGY WITH RECOMMENDATION FOR IMPROVEMENT: Fig. 1.Drug Metabolism and Disposition, 2006
- The Influence of Nonspecific Microsomal Binding on Apparent Intrinsic Clearance, and Its Prediction from Physicochemical PropertiesDrug Metabolism and Disposition, 2002
- Utility of in vitro drug metabolism data in predicting in vivo metabolic clearanceBiochemical Pharmacology, 1994
- Crossvalidation, Bootstrapping, and Partial Least Squares Compared with Multiple Regression in Conventional QSAR StudiesQuantitative Structure-Activity Relationships, 1988