Prediction and evaluation of protein farnesyltransferase inhibition by commercial drugs.
The similarity ensemble approach (SEA) relates proteins based on the set-wise chemical similarity among their ligands. It can be used to rapidly search large compound databases and to build cross-target similarity maps. The emerging maps relate targets in ways that reveal relationships one might not recognize based on sequence or structural similarities alone. SEA has previously revealed cross talk between drugs acting primarily on G-protein coupled receptors (GPCRs). Here we used SEA to look for potential off-target inhibition of the enzyme protein farnesyltransferase (PFTase) by commercially available drugs. The inhibition of PFTase has profound consequences for oncogenesis, as well as a number of other diseases. In the present study, two commercial drugs, Loratadine and Miconazole, were identified as potential ligands for PFTase and subsequently confirmed as such experimentally. These results point toward the applicability of SEA for the prediction of not only GPCR-GPCR drug cross talk but also GPCR-enzyme and enzyme-enzyme drug cross talk.
DeGraw
Amanda J
AJ
Department of Chemistry, University of Minnesota, 207 Pleasant Street SE, Minneapolis, Minnesota 55455, USA.
Keiser
Michael J
MJ
Ochocki
Joshua D
JD
Shoichet
Brian K
BK
Distefano
Mark D
MD
D000818:Animals; D002460:Cell Line; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D051231:Farnesyltranstransferase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D039563:Histamine H1 Antagonists, Non-Sedating / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D008024:Ligands; D017336:Loratadine / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D008825:Miconazole / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D018613:Microscopy, Confocal; D015394:Molecular Structure; D004364:Pharmaceutical Preparations / Q000737:chemistry / Q000378:metabolism; D025941:Protein Interaction Mapping / Q000379:methods; D017368:Protein Prenylation / Q000187:drug effects; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism; D013678:Technology, Pharmaceutical / Q000379:methods; D018631:ras Proteins / Q000235:genetics / Q000378:metabolism
D004791:Enzyme Inhibitors; D039563:Histamine H1 Antagonists, Non-Sedating; D008024:Ligands; D004364:Pharmaceutical Preparations; D011993:Recombinant Fusion Proteins; D049452:Green Fluorescent Proteins; D017336:Loratadine; D008825:Miconazole; D051231:Farnesyltranstransferase; D018631:ras Proteins