title: The Use of Rule-Based and QSPR Approaches in ADME Profiling: A Case Study on Caco-2 Permeability.
abstract: During the early ADME profiling the development of simple, interpretable and reliable in silico tools is very important. In this study, rule-based and QSPR approaches were investigated using a large Caco-2 permeability database. Three permeability classes were determined: high (H), moderate (M) and low (L). The main physicochemical properties related with permeability were ranked as follows: Polar Surface Area (PSA)>Lipophilicity (logP/logD)>Molecular Weight (MW)>number of Hydrogen Bond donors and acceptors>Ionization State>number of Rotatable Bonds>number of Rings. The best rule, based on the combination of PSA-MW-logD (3PRule), was able to identify the H, M and L classes with accuracy of 72.2, 72.9 and 70.6 %, respectively. Subsequently, a consensus system based on three voting binary classification trees was constructed. It accurately predicted 78.4/76.1/79.1 % of H/M/L compounds on training and 78.6/71.1/77.6 % on test set. Finally, the 3PRule and multiclassifier were validated with 23 drugs in a Caco-2 assay. The rule is very useful to improve assay design and prioritize the high absorption candidates. Meanwhile the QSPR model exhibits appropriate classification performance. Due to the simplicity, easy interpretation and accuracy, the 3PRule and consensus model developed here can be used in early ADME profiling.
authors.affiliation: Molecular Simulation & Drug Design Group, Centre of Chemical Bioactive, Central University of Las Villas, Santa Clara 54830, Villa Clara, Cuba phone/fax: 53-42-281192/53-42-281130.
authors.forename: Hai
authors.initials: H
authors.lastname: Pham-The
authors.affiliation: Department of Engineering, Area of Pharmacy and Pharmaceutical Technology, Miguel Hernández University, 03550 Sant Joan d'Alacant, Alicante, Spain.
authors.forename: Isabel
authors.initials: I
authors.lastname: González-Álvarez
authors.affiliation: Department of Engineering, Area of Pharmacy and Pharmaceutical Technology, Miguel Hernández University, 03550 Sant Joan d'Alacant, Alicante, Spain.
authors.forename: Marival
authors.initials: M
authors.lastname: Bermejo
authors.affiliation: Department of Pharmacy and Pharmaceutical Technology, University of Valencia, Burjassot 46100, Valencia, Spain.
authors.forename: Teresa
authors.initials: T
authors.lastname: Garrigues
authors.affiliation: Unit of Computer-Aided Molecular "Biosilico" Discovery and Bioinformatic Research (CAMD-BIR Unit), Faculty of Chemistry-Pharmacy, Central University of Las Villas, Santa Clara, 54830, Villa Clara, Cuba.
authors.forename: Huong
authors.initials: H
authors.lastname: Le-Thi-Thu
authors.affiliation: Molecular Simulation & Drug Design Group, Centre of Chemical Bioactive, Central University of Las Villas, Santa Clara 54830, Villa Clara, Cuba phone/fax: 53-42-281192/53-42-281130. macabreraster@gmail.com, macabrera@uclv.edu.cu.|Department of Engineering, Area of Pharmacy and Pharmaceutical Technology, Miguel Hernández University, 03550 Sant Joan d'Alacant, Alicante, Spain. macabreraster@gmail.com, macabrera@uclv.edu.cu.|Department of Pharmacy and Pharmaceutical Technology, University of Valencia, Burjassot 46100, Valencia, Spain. macabreraster@gmail.com, macabrera@uclv.edu.cu.
authors.forename: Miguel Ángel
authors.initials: MÁ
authors.lastname: Cabrera-Pérez
keywords: ADME profiling; Caco-2 cell permeability; Classification tree; Physicochemical property; Virtual screening