title: A substrate pharmacophore for the human organic cation/carnitine transporter identifies compounds associated with rhabdomyolysis.
abstract: The human organic cation/carnitine transporter (hOCTN2) is a high affinity cation/carnitine transporter expressed widely in human tissues and is physiologically important for the homeostasis of L-carnitine. The objective of this study was to elucidate the substrate requirements of this transporter via computational modeling based on published in vitro data. Nine published substrates of hOCTN2 were used to create a common feature pharmacophore that was validated by mapping other known OCTN2 substrates. The pharmacophore was used to search a drug database and retrieved molecules that were then used as search queries in PubMed for instances of a side effect (rhabdomyolysis) associated with interference with L-carnitine transport. The substrate pharmacophore was composed of two hydrogen bond acceptors, a positive ionizable feature and ten excluded volumes. The substrate pharmacophore also mapped 6 out of 7 known substrate molecules used as a test set. After searching a database of ~800 known drugs, thirty drugs were predicted to map to the substrate pharmacophore with L-carnitine shape restriction. At least 16 of these molecules had case reports documenting an association with rhabdomyolysis and represent a set for prioritizing for future testing as OCTN2 substrates or inhibitors. This computational OCTN2 substrate pharmacophore derived from published data partially overlaps a previous OCTN2 inhibitor pharmacophore and is also able to select compounds that demonstrate rhabdomyolysis, further confirming the possible linkage between this side effect and hOCTN2.
authors.affiliation: Department of Pharmaceutical Sciences, School of Pharmacy, University of Maryland , 20 Penn Street, Baltimore, Maryland 21201, USA. ekinssean@yahoo.com
authors.forename: Sean
authors.initials: S
authors.lastname: Ekins
authors.forename: Lei
authors.initials: L
authors.lastname: Diao
authors.forename: James E
authors.initials: JE
authors.lastname: Polli
mesh_terms: D039301:Computers, Molecular; D064420:Drug-Related Side Effects and Adverse Reactions; D006801:Humans; D027701:Organic Cation Transport Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D004364:Pharmaceutical Preparations / Q000737:chemistry; D012206:Rhabdomyolysis / Q000378:metabolism*; D000074058:Solute Carrier Family 22 Member 5
chemical_list: D027701:Organic Cation Transport Proteins; D004364:Pharmaceutical Preparations; C492020:SLC22A5 protein, human; D000074058:Solute Carrier Family 22 Member 5