title: Highly predictive and interpretable models for PAMPA permeability.
abstract: Cell membrane permeability is an important determinant for oral absorption and bioavailability of a drug molecule. An in silico model predicting drug permeability is described, which is built based on a large permeability dataset of 7488 compound entries or 5435 structurally unique molecules measured by the same lab using parallel artificial membrane permeability assay (PAMPA). On the basis of customized molecular descriptors, the support vector regression (SVR) model trained with 4071 compounds with quantitative data is able to predict the remaining 1364 compounds with the qualitative data with an area under the curve of receiver operating characteristic (AUC-ROC) of 0.90. The support vector classification (SVC) model trained with half of the whole dataset comprised of both the quantitative and the qualitative data produced accurate predictions to the remaining data with the AUC-ROC of 0.88. The results suggest that the developed SVR model is highly predictive and provides medicinal chemists a useful in silico tool to facilitate design and synthesis of novel compounds with optimal drug-like properties, and thus accelerate the lead optimization in drug discovery.
authors.affiliation: National Center for Advancing Translational Sciences (NCATS), National Institutes of Health, Bethesda, MD 20892, USA. Electronic address: sunh7@mail.nih.gov.
authors.forename: Hongmao
authors.initials: H
authors.lastname: Sun
authors.affiliation: National Center for Advancing Translational Sciences (NCATS), National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Kimloan
authors.initials: K
authors.lastname: Nguyen
authors.affiliation: National Center for Advancing Translational Sciences (NCATS), National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Edward
authors.initials: E
authors.lastname: Kerns
authors.affiliation: National Center for Advancing Translational Sciences (NCATS), National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Zhengyin
authors.initials: Z
authors.lastname: Yan
authors.affiliation: National Center for Advancing Translational Sciences (NCATS), National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Kyeong Ri
authors.initials: KR
authors.lastname: Yu
authors.affiliation: National Center for Advancing Translational Sciences (NCATS), National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Pranav
authors.initials: P
authors.lastname: Shah
authors.affiliation: National Center for Advancing Translational Sciences (NCATS), National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Ajit
authors.initials: A
authors.lastname: Jadhav
authors.affiliation: National Center for Advancing Translational Sciences (NCATS), National Institutes of Health, Bethesda, MD 20892, USA. Electronic address: xin.xu3@nih.gov.
authors.forename: Xin
authors.initials: X
authors.lastname: Xu
mesh_terms: D001185:Artificial Intelligence; D018938:Caco-2 Cells; D002463:Cell Membrane Permeability / Q000187:drug effects*; D006801:Humans; D008954:Models, Biological; D009930:Organic Chemicals / Q000737:chemistry / Q000494:pharmacology*; D012044:Regression Analysis; D060388:Support Vector Machine
chemical_list: D009930:Organic Chemicals
keywords: PAMPA; Permeability; Prediction; Support vector machine