Pharmacophore in drug discovery

 

What is Pharmacophore?

A Pharmacophore is an ensemble of steric, electrostatic and hydrophobic properties which is essential for optimal supramolecular interactions with a biolocial receptor, to modulate or inhibit a biological effect. A Pharmacophore does not represent a concrete molecule, but an abstract concept which describes the common molecular properties of interaction with the receptor. The Pharmacophore anchors the agent with the receptor. With pharmacophoric models one can define special properties (pharmacophoric points) based on the structure of the receptor or based on the structure of a known agent. This pharmacophoric points can be checked against a database of pharmacophores.

Pharmacophore approaches have become one of the major tools in drug discovery after the past century's development. Various ligand-based and structure-based methods have been developed for improved pharmacophore modeling and have been successfully and extensively applied in virtual screening, de novo design and lead optimization. Despite these successes, pharmacophore approaches have not reached their expected full capacity, particularly in facing the demand for reducing the current expensive overall cost associated with drug discovery and development.

Typical pharmacophore features include hydrophobic centroids, aromatic rings, hydrogen bond acceptors or donors, 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.

The process for developing a pharmacophore model generally involves the following steps:

1. 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.
2. Conformational analysis – Generate a set of low energy conformations that is likely to contain the bioactive conformation for each of the selected molecules.
3. 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.
4. 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.
5. Validation – A pharmacophore model is a hypothesis accounting for the observed biological activities of a set of molecules that bind to a common biological 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.

Here’s some example of pharmacophore points in drug:

http://www-oc.chemie.uni-regensburg.de/OCP/ch/chv/oc22/script/glossar/Pharmacophore.pdf

Langer, T., and R.D Hoffmann. 2006. Pharmacophores and Pharmacophore Searches.GmbH & Co. KGaA, Weinheim.

Muegge, I. 2002. Pharmacophore features of potential drugs. Chem eur J. Vol 8 (9): 1976-1981.

QUESTION BOX:

1.    Apakah HBD dan HBA selalu berada pada 1 gugus? 2.    Ikatan van der Waals adalah ikatan yang terjadi antara gugus polar dan non-polar (koreksi jika salah). Lantas bagaimana mengidentifikasinya pada struktur? 3.    Ikatan ionik akan berikatan dengan anionic site pada reseptor, apakah selalu demikian?

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