QSAR Model of Unbound Brain-to-Plasma Partition Coefficient, Kp,uu,brain: Incorporating P-glycoprotein Efflux as a Variable.
We report development and prospective validation of a QSAR model of the unbound brain-to-plasma partition coefficient, Kp,uu,brain, based on the in-house data set of ∼1000 compounds. We discuss effects of experimental variability, explore the applicability of both regression and classification approaches, and evaluate a novel, model-within-a-model approach of including P-glycoprotein efflux prediction as an additional variable. When tested on an independent test set of 91 internal compounds, incorporation of P-glycoprotein efflux information significantly improves the model performance resulting in an R2of 0.53, RMSE of 0.57, Spearman's Rho correlation coefficient of 0.73, and qualitative prediction accuracy of 0.8 (kappa = 0.6). In addition to improving the performance, one of the key advantages of this approach is the larger chemical space coverage provided indirectly through incorporation of the in vitro, higher throughput data set that is 4 times larger than the in vivo data set.
Global Scientific Informatics, ‡Advanced Analytics, §Computational ADME, ∥IT Informatics and ⊥Drug Disposition, Lilly Research Laboratories, Eli Lilly and Company , Indianapolis, Indiana 46285, United States.
Elena
E
Dolgikh
Global Scientific Informatics, ‡Advanced Analytics, §Computational ADME, ∥IT Informatics and ⊥Drug Disposition, Lilly Research Laboratories, Eli Lilly and Company , Indianapolis, Indiana 46285, United States.
Ian A
IA
Watson
Global Scientific Informatics, ‡Advanced Analytics, §Computational ADME, ∥IT Informatics and ⊥Drug Disposition, Lilly Research Laboratories, Eli Lilly and Company , Indianapolis, Indiana 46285, United States.
Prashant V
PV
Desai
Global Scientific Informatics, ‡Advanced Analytics, §Computational ADME, ∥IT Informatics and ⊥Drug Disposition, Lilly Research Laboratories, Eli Lilly and Company , Indianapolis, Indiana 46285, United States.
Geri A
GA
Sawada
Global Scientific Informatics, ‡Advanced Analytics, §Computational ADME, ∥IT Informatics and ⊥Drug Disposition, Lilly Research Laboratories, Eli Lilly and Company , Indianapolis, Indiana 46285, United States.
Stuart
S
Morton
Global Scientific Informatics, ‡Advanced Analytics, §Computational ADME, ∥IT Informatics and ⊥Drug Disposition, Lilly Research Laboratories, Eli Lilly and Company , Indianapolis, Indiana 46285, United States.
Timothy M
TM
Jones
Global Scientific Informatics, ‡Advanced Analytics, §Computational ADME, ∥IT Informatics and ⊥Drug Disposition, Lilly Research Laboratories, Eli Lilly and Company , Indianapolis, Indiana 46285, United States.
Thomas J
TJ
Raub
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000097:blood / Q000737:chemistry* / Q000378:metabolism*; D000818:Animals; D001921:Brain / Q000378:metabolism*; D008297:Male; D051379:Mice; D010539:Permeability; D021381:Protein Transport; D021281:Quantitative Structure-Activity Relationship
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1