Pharmacophore modeling, virtual screening, and in vitro testing reveal haloperidol, eprazinone, and fenbutrazate as neurokinin receptors ligands.
Neurokinin receptors (NKRs) have been shown to be involved in many physiological processes, rendering them promising novel drug targets, but also making them the possible cause for side effects of several drugs. Aiming to answer the question whether the binding to NKRs could have a share in the side effects or even the desired effects of already licensed drugs, we generated a set of ligand-based common feature pharmacophore models based on the structural information about subtype-selective and nonselective NKR antagonists and screened an in-house database mainly composed of licensed drugs. The prospective pharmacological investigations of the virtual hits haloperidol, eprazinone, and fenbutrazate confirmed them to be NKR ligands in vitro. By the identification of licensed drugs as so far unknown NKR ligands, this study contributes to establishing an activity profile of the investigated compounds and confirms the presented pharmacophore models as useful tools for this purpose.
Institute of Pharmacy/Pharmacognosy, ‡Institute of Pharmacy/Pharmaceutical Chemistry/CAMD Group, §Institute of Pharmacy/Pharmacology and Toxicology, University of Innsbruck and Center for Molecular Biosciences Innsbruck (CMBI) , Center for Chemistry and Biomedicine (CCB), Innrain 80-82, A-6020 Innsbruck, Austria.
Yvonne
Y
Krautscheid
Carl Johann Åke
CJ
Senning
Simone B
SB
Sartori
Nicolas
N
Singewald
Daniela
D
Schuster
Hermann
H
Stuppner
D062313:Databases, Pharmaceutical; D055808:Drug Discovery; D006220:Haloperidol / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D008024:Ligands; D008958:Models, Molecular; D010654:Phenylbutyrates / Q000737:chemistry / Q000494:pharmacology*; D011427:Propiophenones / Q000737:chemistry / Q000494:pharmacology*; D018039:Receptors, Tachykinin / Q000037:antagonists & inhibitors* / Q000378:metabolism
D008024:Ligands; D010654:Phenylbutyrates; D011427:Propiophenones; D018039:Receptors, Tachykinin; C007608:eprazinone; C012318:fenbutrazate; D006220:Haloperidol