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Applying thermodynamic profiling in lead finding and optimization

Nature Reviews Drug Discovery volume 14, pages 95–110 (2015)Cite this article

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Abstract

Small-molecule drug discovery involves the optimization of various physicochemical properties of a ligand, particularly its binding affinity for its target receptor (or receptors). In recent years, there has been growing interest in using thermodynamic profiling of ligand–receptor interactions in order to select and optimize those ligands that might be most likely to become drug candidates with desirable physicochemical properties. The thermodynamics of binding is influenced by multiple factors, including hydrogen bonding and hydrophobic interactions, desolvation, residual mobility, dynamics and the local water structure. This article discusses key issues in understanding the effects of these factors and applying this knowledge in drug discovery.

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Figure 1: ITC data plotted onto an enthalpy–entropy diagram.
Figure 2: Thermodynamic signatures for congeneric ligand series.
Figure 3: The influence of water molecules in binding pockets on the thermodynamic signature of protein–ligand binding.
Figure 4: Thermodynamic contributions of hydrogen bonds to protein–ligand complex formation.
Figure 5: Cooperative effects in protein–ligand binding.

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Acknowledgements

The author is grateful to the European Commission for a generous European Research Council (ERC) Advanced Grant (DrugProfilBind No. 268145), which made these systematic studies possible. Many members of the Marburg research team have contributed to the reported work. Their effort and engagement — in particular that of B. Baum, A. Biela, A. Heine and S. Krimmer — are highly appreciated.

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Authors and Affiliations

  1. Institute of Pharmaceutical Chemistry, University of Marburg, Marbacher Weg 6, Marburg, D35032, Germany

    Gerhard Klebe

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Correspondence to Gerhard Klebe.

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Supplementary information

Supplementary information S1 (box)

ITC versus van't Hoff data and determination of heat capacity changes ΔCp (PDF 1222 kb)

Supplementary information S2 (figure)

Congeneric series of thermolysin inhibitors with a terminal carboxylate group and with P2′ substituents of growing hydrophobicity (R= H to benzyl). (PDF 382 kb)

Supplementary information S3 (figure)

Congeneric series of thermolysin inhibitors without a terminal carboxylate group and with P2′ substituents of growing hydrophobicity. (PDF 1327 kb)

PowerPoint slides

Glossary

Bioisosteric groups

Chemical groups that have a different chemical composition but elicit the same biological response once they are attached to a basic scaffold and bound to the target protein.

Classical hydrophobic effect

The tendency of non-polar molecules to aggregate and repel water. The effect is measured by the surface area of hydrophobic patches that is removed from solvent access, and it is usually explained as an entropy-driven process, as when the hydrophobic surface becomes buried it displaces water molecules.

Congeneric

In a congeneric series of ligands, one property, such as the size of a hydrophobic substituent, is gradually increased from ligand to ligand.

Difference electron density

X-rays are diffracted at the electrons of the molecules forming a crystal. Therefore, crystallography determines an electron density in the crystal to which a molecular model is fitted. Residual density — so-called 'difference electron density' — not explained by the atoms of the protein, indicates, for example, bound ligands or water molecules.

Enthalpic efficiency

A ligand parameter that, similarly to ligand efficiency, relates the enthalpic binding component of a ligand to its molecular size. Accordingly, the enthalpic binding signal is divided by the number of non-hydrogen atoms that compose the ligand.

Ligand efficiency

A parameter that relates the affinity of a ligand to its molecular size. Various equations to calculate ligand efficiency have been proposed: for example, dividing the Gibbs free energy of binding by the number of non-hydrogen atoms that compose the ligand.

Scaffold

The central molecular core of a lead compound, onto which different substituents and functional groups are attached.

Surface patch increment

The area of the hydrophobic surface of a ligand that becomes buried in the hydrophobic pocket of a protein upon the formation of a protein–ligand complex, contributing to affinity. This description follows the ideas of the classical hydrophobic effect.

Thrombin's 60-loop

Unlike other members of the trypsin-like serine proteases, thrombin has an additional loop that covers the S2 pocket of the protease and has an important influence on the selective recognition of the substrate.

Trajectory

A record along a molecular dynamics simulation of all the geometrical and conformational changes of the simulated system with time.

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Klebe, G. Applying thermodynamic profiling in lead finding and optimization. Nat Rev Drug Discov 14, 95–110 (2015). https://doi.org/10.1038/nrd4486

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