Pharmacophore

In medicinal chemistry and molecular biology, a pharmacophore is an abstract description of molecular features that are necessary for molecular recognition of a ligand by a biological macromolecule. 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 de novo 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 donors, cations, and anions. These pharmacophobic 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.