A look at ligand binding thermodynamics in drug discovery

ABSTRACT

Introduction: 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.

KEYWORDS:

• Binding adaptability
• binding affinity
• binding selectivity
• enthalpy
• entropy
• Gibbs energy
• isothermal titration calorimetry
• ligand binding
• ligand optimization
• lipophilic efficiency
• thermodynamics

Article highlights

• The thermodynamic binding profile (Gibbs energy, enthalpy and entropy of binding) provides a wealth of information on the lead-target interaction due to the high sensitivity of the apparent binding parameters to intrinsic and extrinsic factors.

• Thermodynamic ligand binding data seem to be underutilized in lead selection and optimization in drug discovery programs, and it may prove fundamental for the discovery of new drugs and the reduction of attrition rates when used in combination with biochemical, kinetic, structural, preclinical, and computational data.

• Traditionally lead optimization has been accomplished by optimizing binding entropy: increasing hydrophobicity and conformational rigidity in the ligand. This usually results in poor drug-like ADMET-related properties (e.g., solubility, bioavailability, toxicity).

• Binding enthalpy is related to binding affinity, selectivity, adaptability and drug-like properties. In particular, binding enthalpy seems to be correlated with lipophilic efficiency, a commonly used index for lead optimization rewarding binding affinity and penalizing hydrophobicity.

• Enthalpic optimization leads to better prioritization and optimization of leads, facilitating binding selectivity and adaptability, without compromising other drug-like ADMET-related properties.

• The use of thermodynamic binding profiles requires carefully planned experimental strategy, high-quality experimental data, and good data analysis procedures.

This box summarizes key points contained in the article.

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Additional information

Funding

This article was supported by the Spanish Ministerio de Economía y Competitividad [grants BFU2013-47064-P and BFU2016-78232-P to A Velazquez-Campoy], the Fondo de Investigaciones Sanitarias from the Instituto de Salud Carlos III [grant PI15/00663 to O Abian], the Spanish Ministerio de Educacion, Cultura y Deporte [grant FPU13/3870 to R Claveria-Gimeno], the Miguel Servet Program from Instituto de Salud Carlos III [grant CPII13/0017 to O Abian], the Diputacion General de Aragon [grant B136/13 to R Claveria-Gimeno, Digestive Pathology Group B01 to O Abian and R Claveria-Gimeno, and Protein Targets Group B89 to A Velazquez-Campoy], the Centro de Investigacion Biomedica en Red en Enfermedades Hepaticas y Digestivas (CIBERehd), and the Asociacion Española de Gastroenterologia (AEG).