Pharmacophore

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An example of a pharmacophore model.

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".[1] 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.

Contents

Features [edit]

Superposition of the chemical structures of a benzodiazepine and nonbenzodiazepine ligand and their interactions with binding sites within the receptor.
An example of a pharmacophore model of the benzodiazepine binding site on the GABAA receptor.[2] White sticks represent the carbon atoms of the benzodiazepine diazepam, while green represents carbon atoms of the nonbenzodiazepine CGS-9896. Red and blue sticks are oxygen and nitrogen atoms that are present in both structures. The red spheres labeled H1 and H2/A3 are, respectively, hydrogen bond donating and accepting sites in the receptor, while L1, L2, and L3 denote lipophilic binding sites.

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.

Applications [edit]

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.

History [edit]

Historically, pharmacophores were established by Lemont Kier, who first mentions the concept in 1967[3] and uses the term in a publication in 1971.[4]

The development of the concept is often erroneously accredited to Paul Ehrlich. However neither the alleged source[5] nor any of his other works mention the term "pharmacophore" or make use of the concept.[6]

See also [edit]

References [edit]

  1. ^ Wermuth CG, Ganellin CR, Lindberg P, Mitscher LA (1998). "Glossary of terms used in medicinal chemistry (IUPAC Recommendations 1998)". Pure and Applied Chemistry 70 (5): 1129–1143. doi:10.1351/pac199870051129. 
  2. ^ 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. 
  3. ^ Kier LB (September 1967). "Molecular orbital calculation of preferred conformations of acetylcholine, muscarine, and muscarone". Mol. Pharmacol. 3 (5): 487–94. PMID 6052710. 
  4. ^ Kier LB (1971). Molecular orbital theory in drug research. Boston: Academic Press. pp. 164–169. ISBN 0-12-406550-3. 
  5. ^ Ehrlich P (1909). "Über den jetzigen Stand der Chemotherapie". Ber. Dtsch. Chem. Ges. 42: 17–47. 
  6. ^ J.H. van Drie (2007). "Monty Kier and the Origin of the Pharmacophore Concept". Internet Electronic Journal of Molecular Design 6: 271–279. 

Further reading [edit]

  • Güner OF, ed. (1999). Pharmacophore perception, development, and use in drug design. LaJolla, CA: International University Line. ISBN 0-9636817-6-1. 
  • Langer T, Hoffmann RD (2006). Pharmacophores and pharmacophore searches. Weinheim: WILEY-VCH. ISBN 3-527-31250-1. 

External links [edit]

The following computer software packages enable the user to model the pharmacophore using a variety of computational chemistry methods:
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