Brief Introduction about Pharmacophore You May Want to Know

Pharmacophores are a combination of three-dimensional structural elements that characterize and can be divided into two types. One class is analogs that have the same pharmacological effects. They have a basic structure, that is, the same chemical structure, such as sulfonamides, local anesthetics, receptor blockers, adrenergic drugs, etc.; the other is a group of molecules with completely different chemical structures, but they bind to the same receptor with the same mechanism and produce the same pharmacological effects. For example, diethylstilbestrol has a relatively simple chemical structure, but its steric conformation is similar to that of estradiol. It also has estrogen-like effects.

Pharmacophore theory

Pharmacophores are models based on pharmacodynamic characteristics. The pharmacodynamic characteristic elements are mainly divided into seven types, including: hydrogen bond donors, hydrogen bond acceptors, positive and negative charge centers, aromatic ring centers, hydrophobic groups, hydrophilic groups, and geometric conformational volume collisions.

An effective pharmacophore model generally contains 3–5 effective pharmacophore elements. If the number of pharmacophore elements contained in the model is too large, it may lead to no result in the application of the pharmacophore model.

Origin

When the drug molecule interacts with the target of the receptor, it must have a geometrically matched and energy-matched active conformation with the target. Drug chemists have found that the influence of groups in drug molecules on the activity is different, and changes in some groups have a great influence on the interaction between drugs and targets, while others have little effect. For the study of this difference, it was found that molecules with the same activity often have the same certain characteristics. Therefore, the concept of pharmacophores has been proposed to clarify those features that have important contributions to activity. This concept was first proposed by Paul Ehrlich in 1909 when he proposed that pharmacophores refer to the molecular framework of atoms that have the essential characteristics of activity. In 1977, Peter Gund further defined the concept of pharmacophores as “a group of molecules that recognize receptors and can form structural features of molecular biological activity”. Although the definition latter has changed slightly, people have basically reached a consensus on the connotation of the pharmacophore. In general, it refers to the spatial arrangement of structural features that plays an important role in activity.

Pharmacophore identification

There are two main methods for the identification of pharmacophores. One is based on the structural information of receptors, analyzing the mode of action of receptors and drug molecules to deduce the possible pharmacophore structure; The other is to study the pharmacophores of a series of compounds with unknown or unknown mechanism of receptor structure, and to summarize information of some groups that play a key role in the activity of the compounds through conformation analysis, molecular superposition and other methods. The pharmacophore recognizing process based on the structure of the active compound generally selects the active compound first, selects the molecule suitable for constructing the model, and then uses the conformation analysis to find the binding conformation of the molecule, and superposes the results of the conformation analysis from the superposition. And the pharmacophore was determined from the stacking results.

Application

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