Ligand–Receptor Binding Kinetics in Drug Design

• Published in: Biochemistry (Moscow). Supplement. Series B, Biomedical chemistry Vol. 14; no. 3; pp. 228 - 240
• Main Authors: Borisov, D. V., Veselovsky, A.V.
• Format: Journal Article
• Language: English
• Published: Moscow Pleiades Publishing 01.07.2020; Springer Nature B.V
• Subjects: Affinity; Bioorganic Chemistry; Chemistry; Chemistry and Materials Science; Drug development; Ligands; Medicinal Chemistry; thermodynamics; protein-ligand complex; binding constant; residence time; kinetics; rate constant
• ISSN: 1990-7508; 1990-7516
• DOI: 10.1134/S199075082003004X

Traditionally, the thermodynamic affinity is considered as the main criterion for the development of new drugs. In most cases these thermodynamic affinity values are evaluated in vitro at constant concentrations of a ligand and its receptor, which differ from in vivo conditions of drug action. Recent studies have shown that the kinetics of drug binding to its receptor can be as important as affinity in assessing the drug effectiveness. This significantly increased the interest to receptor–ligand kinetics, particularly in determining the association and dissociation rate constants of receptor-ligand complexes at the stage of preclinical studies of drug candidates. A drug with a longer residence time can kinetically determine ligand selectivity and act at low concentrations in the organism. Here we consider the theoretical principles of protein-ligand binding, molecular determinants, which control the drug-receptor binding kinetics. Understanding the molecular features underlying the receptor-protein binding kinetics will contribute to the rational design of drugs with desired properties.