Structural Determinants of Drug Action
A. Structural specificity is conferred by physical and chemical characteristics, or physicochemical properties, of drugs that allow for specific binding and modulation of the target receptor. These physicochemical properties of a drug are influenced by the acid–base character, water solubility, and stereochemistry, which are dependent on the chemical structure. The physicochemical properties are also important for absorption, distribution, metabolism, and excretion. This structure-to-function connection is the basis for structure–activity relationships (SARs) that are defined by changing the chemical structure and determining its influence on biological activity.
B. Pharmacophore is a term used to describe the critical organic functional groups and their spatial relationship within a drug molecule required for a specific pharmacological activity. Drugs with similar structure and the same pharmacophore typically have similar pharmacological activity but may have other ADME characteristics or potencies that distinguish them from one another.
C. A functional group is a specific group of atoms that have a distinctive acid–base character, contribution to water solubility, and chemical reactivity. The combination of multiple functional groups can influence the properties of adjacent functional groups and together define the physicochemical properties of the drug molecule. Common functional groups are shown in below Tables:
Table 1: Neutral Functional Groups
Table 2: Acidic Functional Groups
Table 3: Basic Functional Groups
D. A bioisostere is a compound containing an atom or group of atoms that is spatially and electronically similar to another molecule that produces a similar biological activity. The goal of bioisosteric replacement is frequently to increase potency, decrease side effects, separate biological activities, or increase the duration of action by altering metabolism. Additionally, bioisosteric substitutions may result in a compound that is an antagonist or inhibitor of the parent molecule; for example, allopurinol (Zyloprim®) inhibits xanthine oxidase, which, through a multistep metabolic process, converts hypoxanthine to uric acid.
E. The stereochemistry of a drug molecule also contributes to the structural specificity of a drug by defining the three-dimensional spatial arrangement of the functional groups required for receptor interactions. Stereoisomers have the same atoms and connectivity but different arrangements in space. Stereoisomers can be divided into three main groups: enantiomers; diastereomers, including geometric isomers; and conformational isomers.
1. Enantiomers are nonsuperimposable mirror images of each other because they contain at least one asymmetric, or chiral, center, usually a carbon covalently bound to four different substituents. A drug containing one chiral carbon can exist in one of two nonsuperimposable isomeric forms, although a drug with multiple chiral centers (n) has the potential to exist in one of 2n isomeric forms that are enantiomers or diastereomers.
2. Diastereomers are stereoisomers that are not enantiomers. More specifically, they are stereoisomers that are not mirror images of each other or superimposable.
3. Conformational isomers, also known as rotamers or conformers, are nonsuperimposable orientations of a molecule that results from the free rotation of atoms around a single bond. Almost every drug can exist in more than one conformation, and this ability allows many drugs to bind to multiple receptors and receptor subtypes.
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