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.
Process for pharmacophore model development
The process for developing a pharmacophore model generally involves the following steps:
- Select a set of molecules
Select a set of molecules that will be used for developing the pharmacophore model. As a pharmacophore model should be able to discriminate between molecules with and without bioactivity, the set of molecules should include both active and inactive compounds.
- Conformational analysis
Perform conformational analysis of the individual molecules and select a presumed bioactive conformation for each. For a pharmacophore model to be valid, the proposed bioactive conformation of a molecule should be a low-energy conformation.
- Molecular superimposition
Superimpose ("fit") the low-energy conformations of the molecules. Similar functional groups common to all molecules in the set might be fitted (e.g., phenyl rings or carboxylic acid groups).
- Abstract description
Transform the superimposed molecules into an abstract representation. For example, superimposed phenyl rings might be referred to more conceptually as an 'aromatic ring' pharmacophore element. Likewise, hydroxy groups could be designated as a 'hydrogen-bond donor/acceptor' pharmacophore element.
A pharmacophore model is basically a hypothesis accounting for the observed biological activities of a set of molecules. The model is only valid insofar as it is able to account for differences in biological activity of a range of molecules.
As the biological activities of new molecules become available, the pharmacophore model can be updated to further refine it.
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.
Pharmacophores are also used as the starting point for developing 3D-QSAR models.
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. doi:10.1002/cber.19090420105.
- 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: