Inmedicinal chemistry andmolecular biology, apharmacophore is an abstract description ofmolecular features that are necessary formolecular recognition of aligand by a biologicalmacromolecule.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 commonreceptor site. Furthermore, pharmacophore models can be used to identify throughde novo design orvirtual screening novel ligands that will bind to the same receptor.
An example of a pharmacophore model of thebenzodiazepine binding site on theGABAA receptor.[2] White sticks represent the carbon atoms of the benzodiazepinediazepam, while green represents carbon atoms of the nonbenzodiazepineCGS-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 denotelipophilic binding sites.
Typical pharmacophore features includehydrophobic centroids,aromatic rings,hydrogen bond acceptors or donors,cations, andanions. These pharmacophore 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.
The process for developing a pharmacophore model generally involves the following steps:
Select a training set of ligands – Choose a structurally diverse 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 – Generate a set of low energy conformations that is likely to contain the bioactive conformation for each of the selected molecules.
Molecular superimposition – Superimpose ("fit") all combinations of the low-energy conformations of the molecules. Similar (bioisosteric) functional groups common to all molecules in the set might be fitted (e.g., phenyl rings or carboxylic acid groups). The set of conformations (one conformation from each active molecule) that results in the best fit is presumed to be the active conformation.
Abstraction – 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.
Validation – A pharmacophore model is ahypothesis accounting for the observed biological activities of a set of molecules that bind to a commonbiological target. 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 moderncomputational chemistry, pharmacophores are used to define the essential features of one or more molecules with the samebiological activity. A database of diversechemical 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 developing3D-QSAR models. Such tools and a related concept of "privileged structures", which are "defined as molecular frameworks which are able of providing useful ligands for more than one type of receptor or enzyme target by judicious structural modifications",[3] aid indrug discovery.[4]
Historically, the modern idea of pharmacophore was popularized byLemont Kier, who mentions the concept in 1967[5] and uses the term in a publication in 1971.[6] Nevertheless,F. W. Shueler, in a 1960s book,[7] uses the expression "pharmacophoric moiety" that corresponds to the modern concept.
The development of the concept is often erroneously accredited toPaul Ehrlich. However neither the alleged source[8] nor any of his other works mention the term "pharmacophore" or make use of the concept.[9]
^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 (ed.).Drug Discovery Handbook. Hoboken, N.J: Wiley-Interscience/J. Wiley. pp. 797–907.ISBN0-471-21384-5.
^Duarte, CD; et al. (2007), "Privileged structures: a useful concept for the rational design of new lead drug candidates",Mini Rev Med Chem,7 (11):1108–1119,doi:10.2174/138955707782331722,PMID18045214.
^Kier LB (September 1967). "Molecular orbital calculation of preferred conformations of acetylcholine, muscarine, and muscarone".Mol. Pharmacol.3 (5):487–94.PMID6052710.
^Kier LB (1971).Molecular orbital theory in drug research. Boston: Academic Press. pp. 164–169.ISBN0-12-406550-3.
^Schueler FW (1960).Chemobiodynamics and Drug Design. McGraw-Hill.
