title: A look at ligand binding thermodynamics in drug discovery.
abstract: Drug discovery is a challenging endeavor requiring the interplay of many different research areas. Gathering information on ligand binding thermodynamics may help considerably in reducing the risk within a high uncertainty scenario, allowing early rejection of flawed compounds and pushing forward optimal candidates. In particular, the free energy, the enthalpy, and the entropy of binding provide fundamental information on the intermolecular forces driving such interaction. Areas covered: The authors review the current status and recent developments in the application of ligand binding thermodynamics in drug discovery. The thermodynamic binding profile (Gibbs energy, enthalpy, and entropy of binding) can be used for lead selection and optimization (binding enthalpy, selectivity, and adaptability). Expert opinion: Binding thermodynamics provides fundamental information on the forces driving the formation of the drug-target complex. It has been widely accepted that binding thermodynamics may be used as a decision criterion along the ligand optimization process in drug discovery and development. In particular, the binding enthalpy may be used as a guide when selecting and optimizing compounds over a set of potential candidates. However, this has been recently called into question by arguing certain difficulties and in the light of certain experimental examples.
authors.affiliation: a Institute of Biocomputation and Physics of Complex Systems (BIFI), IQFR-CSIC-BIFI and GBsC-CSIC-BIFI Joint Units , Universidad de Zaragoza , Zaragoza , Spain.|b Instituto Aragonés de Ciencias de la Salud (IACS) , Zaragoza , Spain.|c Aragon Institute for Health Research (IIS Aragon) , Zaragoza , Spain.
authors.forename: Rafael
authors.initials: R
authors.lastname: Claveria-Gimeno
authors.affiliation: a Institute of Biocomputation and Physics of Complex Systems (BIFI), IQFR-CSIC-BIFI and GBsC-CSIC-BIFI Joint Units , Universidad de Zaragoza , Zaragoza , Spain.
authors.forename: Sonia
authors.initials: S
authors.lastname: Vega
authors.affiliation: a Institute of Biocomputation and Physics of Complex Systems (BIFI), IQFR-CSIC-BIFI and GBsC-CSIC-BIFI Joint Units , Universidad de Zaragoza , Zaragoza , Spain.|b Instituto Aragonés de Ciencias de la Salud (IACS) , Zaragoza , Spain.|c Aragon Institute for Health Research (IIS Aragon) , Zaragoza , Spain.|d Department of Biochemistry and Molecular and Cell Biology , Universidad de Zaragoza , Zaragoza , Spain.|e Centro de Investigación Biomédica en Red en el Área Temática de Enfermedades Hepáticas y Digestivas (CIBERehd) , Barcelona , Spain.
authors.forename: Olga
authors.initials: O
authors.lastname: Abian
authors.affiliation: a Institute of Biocomputation and Physics of Complex Systems (BIFI), IQFR-CSIC-BIFI and GBsC-CSIC-BIFI Joint Units , Universidad de Zaragoza , Zaragoza , Spain.|c Aragon Institute for Health Research (IIS Aragon) , Zaragoza , Spain.|d Department of Biochemistry and Molecular and Cell Biology , Universidad de Zaragoza , Zaragoza , Spain.|e Centro de Investigación Biomédica en Red en el Área Temática de Enfermedades Hepáticas y Digestivas (CIBERehd) , Barcelona , Spain.|f Fundación ARAID , Government of Aragon , Zaragoza , Spain.
authors.forename: Adrian
authors.initials: A
authors.lastname: Velazquez-Campoy
mesh_terms: D000818:Animals; D015195:Drug Design; D055808:Drug Discovery / Q000379:methods*; D019277:Entropy; D006801:Humans; D008024:Ligands; D013816:Thermodynamics
chemical_list: D008024:Ligands
keywords: Binding adaptability; Gibbs energy; binding affinity; binding selectivity; enthalpy; entropy; isothermal titration calorimetry; ligand binding; ligand optimization; lipophilic efficiency; thermodynamics