New Predictive Models for Blood–Brain Barrier Permeability of Drug-like Molecules
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The goals of the present study were to apply a generalized regression model and support vector machine (SVM) models with Shape Signatures descriptors, to the domain of blood–brain barrier (BBB) modeling.
Materials and Methods
The Shape Signatures method is a novel computational tool that was used to generate molecular descriptors utilized with the SVM classification technique with various BBB datasets. For comparison purposes we have created a generalized linear regression model with eight MOE descriptors and these same descriptors were also used to create SVM models.
The generalized regression model was tested on 100 molecules not in the model and resulted in a correlation r 2 = 0.65. SVM models with MOE descriptors were superior to regression models, while Shape Signatures SVM models were comparable or better than those with MOE descriptors. The best 2D shape signature models had 10-fold cross validation prediction accuracy between 80–83% and leave-20%-out testing prediction accuracy between 80–82% as well as correctly predicting 84% of BBB+ compounds (n = 95) in an external database of drugs.
Our data indicate that Shape Signatures descriptors can be used with SVM and these models may have utility for predicting blood–brain barrier permeation in drug discovery.
KEY WORDSblood–brain barrier principal component analysis regression shape signatures support vector machine
absorption, distribution, metabolism and excretion
central nervous system
molecular electrostatic potential
molecular operating environment
principal component analysis
quantitative structure activity relationship
recursive feature elimination
solvent accessible surface
support vector machine
topological polar surface area
unsupervised forward selection
Support for this work has been provided by the USEPA-funded Environmental Bioinformatics and Computational Toxicology Center (ebCTC), under STAR Grant number GAD R 832721-010. WJW gratefully acknowledges support for this work provided by the Defense Threat Reduction Agency, under contract number HDTRA-BB07TAS020. This work was also funded in part by NIH R21-GM081394 from the National Institute of General Medical Sciences and by NIH Integrated Advanced Information Management Systems (IAIMS) Grant # 2G08LM06230-03A1 from the National Library of Medicine. This work has not been reviewed by and does not represent the opinions of the funding agencies. The authors are sincerely grateful to Randy Zauhar, Ph.D., of the University of the Sciences in Philadelphia, for useful discussions on technical aspects of Shape Signatures.
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