Thermodynamic profiling for fragment-based lead discovery and optimization

ABSTRACT

Introduction: The enthalpic and entropic components of the ligand–protein binding free energy reflect the type and quality of the interactions and relate to the physicochemical properties of the ligands. These findings have significance in medicinal chemistry optimizations since they suggest that the thermodynamic profiling of the binding may help monitor and control the unfavorable size and hydrophobicity increase typically accompanying affinity improvements and leading to suboptimal pharmacokinetic properties.

Areas covered: This review describes the ligand–protein binding event in terms of elementary steps, their associated interactions, and their enthalpic and entropic consequences. The relationships among the breaking and forming interactions, the binding thermodynamic profile, and the physicochemical properties of the ligands are also discussed.

Expert opinion: Analysis of the size dependence of available affinity and favorable enthalpy highlights the limitation of the simultaneous optimization of these quantities. Indeed, moderate, rather than very high affinities can be conciliated with favorable physicochemical and pharmacokinetic profiles as it is supported by the affinity range of historical oral drugs. Although thermodynamic quantities are not suitable endpoints for medicinal chemistry optimizations owing to the complexity of the binding thermodynamics, thermodynamic profiling together with structural studies can be advantageously used to understand the details of the binding process and to optimize it.

KEYWORDS:

• Binding thermodynamics
• enthalpy driven optimization
• entropy driven optimization
• fragment binding
• fragment optimization

Article Highlights

• Ligand–protein binding thermodynamics is related to the type and quality of interactions

• Optimal geometry polar interactions provide favorable binding enthalpy

• The desolvation of apolar groups is the major source of favorable binding entropy

• Enthalpy, rather than entropy driven optimizations tend to provide compounds with favorable pharmacokinetic profiles

• Enthalpic optimizations are more challenging than entropic optimizations

• Binding thermodynamic profiling with structural studies supports medicinal chemistry optimizations

• Available ligand affinity shows increasing, and favorable enthalpy shows decreasing trend with ligand size

• Enthalpy dominated binding is a general feature of fragment-sized compounds

• Fragments are well suited for enthalpy driven early optimizations

This box summarizes key points contained in the article.

Declaration of interest

The authors have no other 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 apart from those disclosed.

Reviewer Disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This work was supported by the Hungarian Brain Research Program under Grant 2017-1.2.1-NKP-2017-00002.