A pharmacophore is an abstract description of molecular features which are necessary for molecular recognition of a ligand by a biological macromolecule. The IUPAC defines a pharmacophore to be "an ensemble of steric and electronic features that is necessary to ensure the optimal supramolecular interactions with a specific biological target and to trigger (or block) its biological response". A pharmacophore model explains how structurally diverse ligands can bind to a common receptor site. Furthermore pharmacophore models can be used to identify through denovo design or virtual screening novel ligands that will bind to the same receptor.
Typical pharmacophore features include hydrophobic centroids, aromatic rings, hydrogen bond acceptors or donor, cations, and anions. These pharmacophoric points may be located on the ligand itself or may be projected points presumed to be located in the receptor.
The features need to match different chemical groups with similar properties, in order to identify novel ligands. Ligand-receptor interactions are typically “polar positive”, “polar negative” or “hydrophobic”. A well-defined pharmacophore model includes both hydrophobic volumes and hydrogen bond vectors.
In modern computational chemistry, pharmacophores are used to define the essential features of one or more molecules with the same biological activity. A database of diverse chemical compounds can then be searched for more molecules which share the same features arranged in the same relative orientation.
The development of the concept is often erroneously accredited to Paul Ehrlich. However neither the alleged source nor any of his other works mention the term "pharmacophore" or make use of the concept.
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- Madsen U, Bräuner-Osborne H, Greenwood JR, Johansen TN, Krogsgaard-Larsen P, Liljefors T, Nielsen M, Frølund B (2005). "GABA and Glutamate receptor ligands and their therapeutic potential in CNS disorders". In Gad SC. Drug Discovery Handbook. Hoboken, N.J: Wiley-Interscience/J. Wiley. pp. 797–907. ISBN 0-471-21384-5.
- Kier LB (September 1967). "Molecular orbital calculation of preferred conformations of acetylcholine, muscarine, and muscarone". Mol. Pharmacol. 3 (5): 487–94. PMID 6052710.
- Kier LB (1971). Molecular orbital theory in drug research. Boston: Academic Press. pp. 164–169. ISBN 0-12-406550-3.
- Ehrlich P (1909). "Über den jetzigen Stand der Chemotherapie". Ber. Dtsch. Chem. Ges. 42: 17–47.
- J.H. van Drie (2007). "Monty Kier and the Origin of the Pharmacophore Concept". Internet Electronic Journal of Molecular Design 6: 271–279.
The following computer software packages enable the user to model the pharmacophore using a variety of computational chemistry methods: