Innovative Medicinal Chemistry Strategies for Improving Target Binding Kinetics in Drug Discovery

The concept of drug-target binding kinetics has garnered significant attention in recent drug discovery literature. Incorporating drug-target binding kinetics into the early phases of drug development has resulted in several clinical candidates exhibiting promising efficacy and favorable safety profiles. Nevertheless, optimizing the target binding kinetic properties of pharmaceutical agents remains a notable challenge. For the first time, we herein summarize novel medicinal chemistry strategies for improving drug-target binding kinetics properties, including ligand-based drug design, conformational adaptation, enhancement of aromatic stacking interactions, cyclization strategies, modification of active tolerance site, covalent inhibitor design, disruption of protein water molecule networks, and allosteric inhibitor design. We further describe the structure-kinetics relationships and biological activity of drugs while providing current challenges and perspectives in binding kinetics optimization. Through highlighting residence time modulation strategies, we aim to establish a theoretical framework for rational structural modification, thereby facilitating innovative drug development.