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Pharmacophore modeling of non transported competitive inhibitors of the human Organic Cation Transporter, hOCT1
Author(s) -
Moaddel Ruin,
Ravichandran Sarangan,
Bigi Federica,
Collins Jack,
Yamaguchi Rika,
Wainer Irving W
Publication year - 2007
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.21.6.a1187-b
Subject(s) - pharmacophore , chemistry , organic cation transport proteins , hydrogen bond , acceptor , stereochemistry , transporter , combinatorial chemistry , molecule , organic chemistry , biochemistry , gene , physics , condensed matter physics
Purpose: The development of a pharmacophore to predict and describe binding to the hOCT1 transporter. METHODS: An hOCT1 pharmacophore was generated using catalyst 4.11 and HypoGen and a training set of 22 compounds. The K i values for 17/22 of the compounds were obtained on a chromatography column containing immobilized membrane fragments from a hOCT1‐MDCK cell line and a column containing hOCT1 in which M replaced R at position 488, R488M‐hOCT1. The pharmacophore model was tested using two sets, one containing non‐transported competitive inhibitors and the other transported substrates. RESULTS: The pharmacophore contained positive ionizable, hydrophobic and two hydrogen‐bond acceptor sites. The hypothesis had a correlation factor of 0.855245 and a RMS of 1.00417. Competitive inhibitors mapped to at least three of the four sites and the model was able to correctly estimate their K i ’s. Substrates mapped to two sites and the estimated K i ’s were > 200 μM. Comparison of the K i ’s obtained on the hOCT1 and R488M‐OCT columns indicate that R488 is related to one of the hydrogen‐bond acceptor sites identified in the pharmacophore model. CONCLUSIONS: The pharmacophore predicts and describes binding to the hOCT1 transporter and the location of one of the binding sites has been identified. The model was statistically significant, can be used to estimated K i ’s and to qualitatively identify compounds as inhibitors or substrates.