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Drugs' Secret Weapon: Why Ligand Affinity Matters?
In the fields of biochemistry and pharmacology, ligands are defined as substances that form complexes with biological molecules to achieve biological purposes. According to the Latin root "ligare", the essence of ligand is "to bind". The affinity of a ligand refers to the strength with which the ligand binds to its target protein, and this binding is critical to the drug's effect.
Binding of ligands often results in conformational changes in the target protein, thereby changing its functional state.
In protein-ligand binding, the ligand is usually a molecule capable of generating a signal by binding to a specific site on the target protein. This process involves the interaction of multiple factors such as charge, hydrophobicity and molecular structure. This binding mainly relies on intermolecular forces, including ionic bonds, hydrogen bonds and van der Waals forces. In biological systems, reversible binding between ligands and target molecules is a common phenomenon, while irreversible covalent binding is rare.
The binding affinity of a ligand to a receptor can usually be measured by the inhibition constant Ki.
The interaction between a ligand and its binding site can be characterized by binding affinity. The higher the affinity, the stronger the attraction between the ligand and the receptor. This means that high-affinity ligands are able to achieve maximum binding at lower concentrations, thereby triggering physiological responses.
For example, when a ligand binds to a receptor and causes a physiological response, the ligand is called an inducer; if the ligand fails to activate the receptor, the ligand is called an antagonist. Ligands with higher affinity can often use part of the binding energy to cause conformational changes in the receptor, thereby leading to changes in physiological behavior.
Selective ligands can bind to specific receptors, while non-selective ligands can bind to multiple types of receptors, which is particularly important in pharmacology.
In drug design, selective ligands help reduce side effects because they more precisely target receptors, whereas non-selective ligands may bind to multiple other receptors, leading to an increase in adverse effects. The potency of the ligand and its binding affinity to the receptor together influence the overall potency of the drug.
In addition, composite ligands such as bivalent ligands, which are composed of two drug-like molecules connected through an inactive linker, are increasingly attracting the attention of researchers. This type of ligand can target multiple receptors at the same time, improving the specificity and effectiveness of treatment.
The interplay between ligand affinity and potency plays a crucial role in drug design and development.
With advances in computational chemistry, we now have the ability to use computational tools to conduct in-depth studies of protein-ligand interactions, which not only improves the accuracy of drug design but also accelerates the discovery process of new drugs. With the help of computational chemistry technology of high-performance computers, researchers can simulate the dynamic process of ligand-receptor binding.
Reviewing the diverse methods used to study ligand-receptor interactions, we find that a combination of techniques, from spectroscopy to cryo-electron microscopy methods, can comprehensively improve our understanding of these biological processes. This gives us greater confidence and scientific basis when designing drugs for widespread medical use.
Combining the key parameters of affinity, selectivity and potency, can we more effectively design drugs that can precisely target pathological conditions and minimize the occurrence of side effects?
