Pharmacophore
Definition
A pharmacophore is an abstract description of molecular features which are necessary for molecular recognition of a ligand by a biological macromolecule. The concept was first presented by Paul Ehrlich in 1909. A pharmacophore does not represent a real molecule or a real association of functional groups, but a purely abstract concept that accounts for the common molecular interaction capacities of a group of compounds towards their target structure.
History
The concept of the pharmacophore has its origins in the observations of Paul Ehrlich, who proposed in 1909 that chemicals and substrates bind biological receptors or enzymes via what he called "receptive substances". The pharmacophore concept was refined over the following years by scientists such as J. H. Van't Hoff, O. Capellmann, M. Kopp, F. H. Fischer, and C. D. Leffler.
Characteristics
A pharmacophore is defined by a set of structural features in a molecule that is recognized at a receptor site and is responsible for that molecule's biological activity. In this context, the pharmacophore is the "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".
Types of Pharmacophores
Pharmacophores are usually classified into two types: ligand-based pharmacophores and structure-based pharmacophores.
Ligand-Based Pharmacophores
Ligand-based pharmacophore models are developed from a set of molecules that are known to interact with the target of interest. These models are often used when the 3D structure of the target is not known and a set of ligands that are known to bind to the target are available.
Structure-Based Pharmacophores
Structure-based pharmacophore models are derived from the 3D structure of the target molecule. These models are used when the 3D structure of the target is known and a set of ligands that are known to bind to the target are not available.
Pharmacophore Modeling
Pharmacophore modeling involves the use of computer-aided drug design (CADD) tools to create a 3D representation of the pharmacophore. This model can then be used to screen databases of chemical compounds to identify potential new drugs that have the same or similar pharmacophoric features.
Applications
Pharmacophore models are used in various applications in drug discovery and development. They are used in virtual screening, lead optimization, and drug repurposing. Pharmacophore models can also be used to predict the biological activity of new chemical entities.