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Molecular Requirements of the Human Nucleoside Transporters hCNT1, hCNT2, and hENT1

Biophysics Program, the Ohio State University, Columbus, Ohio (C.C.); Department of Pharmaceutical Sciences, University of Maryland at Baltimore, Baltimore, Maryland (P.W.S.); and Department of Pharmaceutics, University of Washington, Seattle, Washington (L.Y.N., P.Y.L., S.D.P., J.D.U.)

Concentrative nucleoside transporters (CNTs) and equilibrative nucleoside transporters (ENTs) are important in physiological and pharmacological activity and disposition of nucleosides and nucleoside drugs. A better understanding of the structural requirements of inhibitors for these transporters will aid in designing therapeutic agents. To define the relative and unified structural requirements of nucleoside analogs for interaction with hCNT1, hCNT2, and hENT1, we applied an array of structure-activity techniques. Unique pharmacophore models for each respective nucleoside transporter were generated. These models reveal that hCNT2 affinity is dominated by hydrogen bonding features, whereas hCNT1 and hENT1 displayed mainly electrostatic and steric features. Hydrogen bond formation over 3'-OH is essential for all nucleoside transporters. Inhibition of nucleoside transporters by a series of uridine and adenosine analogs and a variety of drugs was analyzed by comparative molecular field analysis. Cross-validated r² (q²) values were 0.65, 0.52, and 0.74 for hCNT1, hCNT2, and hENT1, respectively. The predictive quality of the models was further validated by successful prediction of the inhibition of a set of test compounds. Addition of a hydroxyl group around the 2-position of purine (or 3-position of pyrimidine) may increase inhibition to hCNT2 transporter; addition of hydroxyl group around the 2,7-position of purine (or the 3,5-position of pyrimidine) would increase the inhibition to hENT1 transporter. Utilization of these models should assist the design of high-affinity nucleoside transporter inhibitors and substrates for both anticancer and antiviral therapy.

Address correspondence to: Peter W. Swaan, Department of Pharmaceutical Sciences, University of Maryland, 20 Penn Street, Baltimore, MD 21202. E-mail: pswaan{at}rx.umaryland.edu

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