title: Molecular Properties of Drugs Interacting with SLC22 Transporters OAT1, OAT3, OCT1, and OCT2: A Machine-Learning Approach.
abstract: Statistical analysis was performed on physicochemical descriptors of ∼250 drugs known to interact with one or more SLC22 "drug" transporters (i.e., SLC22A6 or OAT1, SLC22A8 or OAT3, SLC22A1 or OCT1, and SLC22A2 or OCT2), followed by application of machine-learning methods and wet laboratory testing of novel predictions. In addition to molecular charge, organic anion transporters (OATs) were found to prefer interacting with planar structures, whereas organic cation transporters (OCTs) interact with more three-dimensional structures (i.e., greater SP3 character). Moreover, compared with OAT1 ligands, OAT3 ligands possess more acyclic tetravalent bonds and have a more zwitterionic/cationic character. In contrast, OCT1 and OCT2 ligands were not clearly distinquishable form one another by the methods employed. Multiple pharmacophore models were generated on the basis of the drugs and, consistent with the machine-learning analyses, one unique pharmacophore created from ligands of OAT3 possessed cationic properties similar to OCT ligands; this was confirmed by quantitative atomic property field analysis. Virtual screening with this pharmacophore, followed by transport assays, identified several cationic drugs that selectively interact with OAT3 but not OAT1. Although the present analysis may be somewhat limited by the need to rely largely on inhibition data for modeling, wet laboratory/in vitro transport studies, as well as analysis of drug/metabolite handling in Oat and Oct knockout animals, support the general validity of the approach-which can also be applied to other SLC and ATP binding cassette drug transporters. This may make it possible to predict the molecular properties of a drug or metabolite necessary for interaction with the transporter(s), thereby enabling better prediction of drug-drug interactions and drug-metabolite interactions. Furthermore, understanding the overlapping specificities of OATs and OCTs in the context of dynamic transporter tissue expression patterns should help predict net flux in a particular tissue of anionic, cationic, and zwitterionic molecules in normal and pathophysiological states.
authors.affiliation: Departments of Bioengineering (H.C.L.), Pediatrics (A.G., Y.C., C.L., K.T.B., S.K.N.), Medicine (W.W., S.K.N.), Cellular and Molecular Medicine (S.K.N.), and Pharmacology (R.A.), and the San Diego Supercomputer Center (N.B., P.R.), University of California San Diego, La Jolla, California.
authors.forename: Henry C
authors.initials: HC
authors.lastname: Liu
authors.affiliation: Departments of Bioengineering (H.C.L.), Pediatrics (A.G., Y.C., C.L., K.T.B., S.K.N.), Medicine (W.W., S.K.N.), Cellular and Molecular Medicine (S.K.N.), and Pharmacology (R.A.), and the San Diego Supercomputer Center (N.B., P.R.), University of California San Diego, La Jolla, California.
authors.forename: Anne
authors.initials: A
authors.lastname: Goldenberg
authors.affiliation: Departments of Bioengineering (H.C.L.), Pediatrics (A.G., Y.C., C.L., K.T.B., S.K.N.), Medicine (W.W., S.K.N.), Cellular and Molecular Medicine (S.K.N.), and Pharmacology (R.A.), and the San Diego Supercomputer Center (N.B., P.R.), University of California San Diego, La Jolla, California.
authors.forename: Yuchen
authors.initials: Y
authors.lastname: Chen
authors.affiliation: Departments of Bioengineering (H.C.L.), Pediatrics (A.G., Y.C., C.L., K.T.B., S.K.N.), Medicine (W.W., S.K.N.), Cellular and Molecular Medicine (S.K.N.), and Pharmacology (R.A.), and the San Diego Supercomputer Center (N.B., P.R.), University of California San Diego, La Jolla, California.
authors.forename: Christina
authors.initials: C
authors.lastname: Lun
authors.affiliation: Departments of Bioengineering (H.C.L.), Pediatrics (A.G., Y.C., C.L., K.T.B., S.K.N.), Medicine (W.W., S.K.N.), Cellular and Molecular Medicine (S.K.N.), and Pharmacology (R.A.), and the San Diego Supercomputer Center (N.B., P.R.), University of California San Diego, La Jolla, California.
authors.forename: Wei
authors.initials: W
authors.lastname: Wu
authors.affiliation: Departments of Bioengineering (H.C.L.), Pediatrics (A.G., Y.C., C.L., K.T.B., S.K.N.), Medicine (W.W., S.K.N.), Cellular and Molecular Medicine (S.K.N.), and Pharmacology (R.A.), and the San Diego Supercomputer Center (N.B., P.R.), University of California San Diego, La Jolla, California.
authors.forename: Kevin T
authors.initials: KT
authors.lastname: Bush
authors.affiliation: Departments of Bioengineering (H.C.L.), Pediatrics (A.G., Y.C., C.L., K.T.B., S.K.N.), Medicine (W.W., S.K.N.), Cellular and Molecular Medicine (S.K.N.), and Pharmacology (R.A.), and the San Diego Supercomputer Center (N.B., P.R.), University of California San Diego, La Jolla, California.
authors.forename: Natasha
authors.initials: N
authors.lastname: Balac
authors.affiliation: Departments of Bioengineering (H.C.L.), Pediatrics (A.G., Y.C., C.L., K.T.B., S.K.N.), Medicine (W.W., S.K.N.), Cellular and Molecular Medicine (S.K.N.), and Pharmacology (R.A.), and the San Diego Supercomputer Center (N.B., P.R.), University of California San Diego, La Jolla, California.
authors.forename: Paul
authors.initials: P
authors.lastname: Rodriguez
authors.affiliation: Departments of Bioengineering (H.C.L.), Pediatrics (A.G., Y.C., C.L., K.T.B., S.K.N.), Medicine (W.W., S.K.N.), Cellular and Molecular Medicine (S.K.N.), and Pharmacology (R.A.), and the San Diego Supercomputer Center (N.B., P.R.), University of California San Diego, La Jolla, California.
authors.forename: Ruben
authors.initials: R
authors.lastname: Abagyan
authors.affiliation: Departments of Bioengineering (H.C.L.), Pediatrics (A.G., Y.C., C.L., K.T.B., S.K.N.), Medicine (W.W., S.K.N.), Cellular and Molecular Medicine (S.K.N.), and Pharmacology (R.A.), and the San Diego Supercomputer Center (N.B., P.R.), University of California San Diego, La Jolla, California snigam@ucsd.edu.
authors.forename: Sanjay K
authors.initials: SK
authors.lastname: Nigam
mesh_terms: D019295:Computational Biology / Q000379:methods*; D006863:Hydrogen-Ion Concentration; D000069550:Machine Learning; D026901:Membrane Transport Proteins / Q000737:chemistry / Q000378:metabolism*; D008958:Models, Molecular; D027362:Organic Anion Transport Protein 1 / Q000737:chemistry / Q000378:metabolism; D029362:Organic Anion Transporters, Sodium-Independent / Q000737:chemistry / Q000378:metabolism; D027702:Organic Cation Transporter 1 / Q000737:chemistry / Q000378:metabolism; D004364:Pharmaceutical Preparations / Q000737:chemistry / Q000378:metabolism*; D011485:Protein Binding; D011487:Protein Conformation; D013379:Substrate Specificity
chemical_list: D026901:Membrane Transport Proteins; D027362:Organic Anion Transport Protein 1; D029362:Organic Anion Transporters, Sodium-Independent; D027702:Organic Cation Transporter 1; D004364:Pharmaceutical Preparations