title: Towards Better BBB Passage Prediction Using an Extensive and Curated Data Set.
abstract: In the present report, the challenging task of drug delivery across the blood-brain barrier (BBB) is addressed via a computational approach. The BBB passage was modeled using classification and regression schemes on a novel extensive and curated data set (the largest to the best of our knowledge) in terms of log BB. Prior to the model development, steps of data analysis that comprise chemical data curation, structural, cutoff and cluster analysis (CA) were conducted. Linear Discriminant Analysis (LDA) and Multiple Linear Regression (MLR) were used to fit classification and correlation functions. The best LDA-based model showed overall accuracies over 85 % and 83 % for the training and test sets, respectively. Also a MLR-based model with acceptable explanation of more than 69 % of the variance in the experimental log BB was developed. A brief and general interpretation of proposed models allowed the estimation on how 'near' our computational approach is to the factors that determine the passage of molecules through the BBB. In a final effort some popular and powerful Machine Learning methods were considered. Comparable or similar performance was observed respect to the simpler linear techniques. Most of the compounds with anomalous behavior were put aside into a set denoted as controversial set and discussion regarding to these compounds is provided. Finally, our results were compared with methodologies previously reported in the literature showing comparable to better results. The results could represent useful tools available and reproducible by all scientific community in the early stages of neuropharmaceutical drug discovery/development projects.
authors.affiliation: Vancouver Prostate Centre, University of British Columbia, Vancouver, British Columbia, V6H 3Z6, Canada.|Unit of Computer-Aided Molecular "Biosilico" Discovery and Bioinformatic Research, International Network (CAMD-BIR International Network), Los Laureles L76MD, Nuevo Bosque, 130015, Cartagena de Indias, Bolivar, Colombia. Homepage: http://www.uv.es/yoma/ Homepage: http://sites.google.com/site/ymponce/home.
authors.forename: Yoan
authors.initials: Y
authors.lastname: Brito-Sánchez
authors.affiliation: Unit of Computer-Aided Molecular "Biosilico" Discovery and Bioinformatic Research, International Network (CAMD-BIR International Network), Los Laureles L76MD, Nuevo Bosque, 130015, Cartagena de Indias, Bolivar, Colombia. Homepage: http://www.uv.es/yoma/ Homepage: http://sites.google.com/site/ymponce/home. ymarrero77@yahoo.es.|Grupo de Investigación en Estudios Químicos y Biológicos, Facultad de Ciencias Básicas, Universidad Tecnológica de Bolívar, Parque Industrial y Tecnológico Carlos Vélez Pombo Km 1 vía Turbaco, 130010, Cartagena de Indias, Bolívar, Colombia. ymarrero77@yahoo.es.|Facultad de Química Farmacéutica, Universidad de Cartagena, Cartagena de Indias, Bolívar, Colombia. ymarrero77@yahoo.es.
authors.forename: Yovani
authors.initials: Y
authors.lastname: Marrero-Ponce
authors.affiliation: Unit of Computer-Aided Molecular "Biosilico" Discovery and Bioinformatic Research, International Network (CAMD-BIR International Network), Los Laureles L76MD, Nuevo Bosque, 130015, Cartagena de Indias, Bolivar, Colombia. Homepage: http://www.uv.es/yoma/ Homepage: http://sites.google.com/site/ymponce/home.|Department of Chemistry, Federal University of Lavras, P.O. Box 3037, 37200-000, Lavras, MG, Brazil.
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Barigye
authors.affiliation: Grupo de Investigación en Estudios Químicos y Biológicos, Facultad de Ciencias Básicas, Universidad Tecnológica de Bolívar, Parque Industrial y Tecnológico Carlos Vélez Pombo Km 1 vía Turbaco, 130010, Cartagena de Indias, Bolívar, Colombia.
authors.forename: Iván
authors.initials: I
authors.lastname: Yaber-Goenaga
authors.affiliation: Center of Studies on Informatics, Universidad "Marta Abreu" de Las Villas, Santa Clara, 54830, Villa Clara, Cuba.
authors.forename: Carlos
authors.initials: C
authors.lastname: Morell Pérez
authors.affiliation: School of Medicine and Pharmacy, Vietnam National University, Hanoi (VNU) 144 Xuan Thuy, CauGiay, Hanoi, Vietnam.
authors.forename: Huong
authors.initials: H
authors.lastname: Le-Thi-Thu
authors.affiliation: Vancouver Prostate Centre, University of British Columbia, Vancouver, British Columbia, V6H 3Z6, Canada.
authors.forename: Artem
authors.initials: A
authors.lastname: Cherkasov
mesh_terms: D000818:Animals; D001812:Blood-Brain Barrier / Q000502:physiology*; D003198:Computer Simulation; D006801:Humans; D008955:Models, Cardiovascular; D008959:Models, Neurological
keywords: BBB endpoint; Bloodbrain barrier; Dragon descriptor; Linear discriminant analysis; Multiple linear regression; P-glycoprotein; Quantitative structure pharmacokinetic (property) relationship