Expert opinion on drug discovery · 2026
Current applications of isothermal titration calorimetry for lead optimization.
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Hu Huiyang, Guerrero Martin, Bao Yuping
Аннотация
INTRODUCTION: Isothermal titration calorimetry (ITC) is a valuate technique for drug lead optimization by providing a complete thermodynamic profile of ligand-target interactions. ITC further provides mechanistic insights into binding by distinguishing enthalpy and entropy for improved binding affinity and selectivity.
AREA COVERED: This review focuses on ITC applications in thermodynamic and kinetic information informed lead optimization using representative examples. Here, ITC's roles in optimizing binding affinity, selectivity, and binding mechanisms were emphasized. Practical considerations, current limitations, and emerging opportunities for integrating ITC with structural biology and computational approaches are also discussed. The literature was identified through searches of Web of Science and Google Scholar using keywords related to isothermal titration calorimetry, drug lead optimization, and thermodynamics-guided medicinal chemistry (2018-2026) with the inclusion of earlier literature on ITC fundamentals.
EXPERT OPINION: ITC has been evolving from a specialized biophysical method into a central platform for lead optimization. Beyond thermodynamic parameters, recent advancements, including kinetic ITC, microfluidic ITC, and enhanced data analysis, have significantly expanded its capabilities. The greatest impact of ITC is achieved when integrated with structural, computational, and biological approaches, enabling a comprehensive understanding of molecular recognition and facilitating the development of drug candidates with enhanced potency, selectivity, and favorable binding mechanisms.
AREA COVERED: This review focuses on ITC applications in thermodynamic and kinetic information informed lead optimization using representative examples. Here, ITC's roles in optimizing binding affinity, selectivity, and binding mechanisms were emphasized. Practical considerations, current limitations, and emerging opportunities for integrating ITC with structural biology and computational approaches are also discussed. The literature was identified through searches of Web of Science and Google Scholar using keywords related to isothermal titration calorimetry, drug lead optimization, and thermodynamics-guided medicinal chemistry (2018-2026) with the inclusion of earlier literature on ITC fundamentals.
EXPERT OPINION: ITC has been evolving from a specialized biophysical method into a central platform for lead optimization. Beyond thermodynamic parameters, recent advancements, including kinetic ITC, microfluidic ITC, and enhanced data analysis, have significantly expanded its capabilities. The greatest impact of ITC is achieved when integrated with structural, computational, and biological approaches, enabling a comprehensive understanding of molecular recognition and facilitating the development of drug candidates with enhanced potency, selectivity, and favorable binding mechanisms.