A deep understanding of ligand-protein binding energetics is considered fundamental for Medicinal Chemistry as it underpins approaches for potency optimization of chemical leads through rational structural modification. Despite this importance, and the recent advances in structural biology and computational chemistry, our understanding of structure-activity relationships (SAR) at a molecular level is often incomplete. This is a source of inefficiency in drug discovery projects since SAR frequently needs to be gained by trial and error. Use of modern biophysical methods such as isothermal titration calorimetry (ITC) - which enable ligand binding free energy (ΔGbind) to be factorized into entropic (TΔSbind) and enthalpic (ΔHbind) components – have been suggested as tools to drive increased understanding of the intermolecular forces that drive SAR. The hope is to improve efficiency in medicinal chemistry by increasing the probability that a chosen structural modification to a lead molecule will result in increased potency and improvements in other lead quality attributes. Recently, a viewpoint has emerged that ligands which have a greater contribution of ΔHbind to their overall ΔGbind (herein termed %ΔHbind) are preferred as drugs and drug leads. The concept appears to be based on an extrapolation of the accepted wisdom that the classical hydrophobic effect (why oil and water do not mix) is inherently entropic in nature. If one then assumes that hydrophobic ligand-protein interactions are also generally ΔSbind based, and that the opposite is true for polar interactions and ΔHbind, then a logical progression may be that lipophilic efficiency (LipE; pKi-logD) correlates with %ΔHbind. Such a relationship would link ligand binding thermodynamic signatures with deeper aspects of lead quality beyond potency, such as selectivity and pharmacokinetics The presentation will focus primarily on a detailed analysis of published binding thermodynamics data for small molecule-protein binding events. I will examine whether data support a high %ΔHbind being a favorable lead property and whether thermodynamic signatures can aid lead optimization campaigns. In addition, my presentation will highlight the many factors – both experimental and structural – which may influence thermodynamic binding signatures determined by ITC. I will also provide an overview of the importance and ubiquity of entropy-enthalpy compensation in protein-ligand binding energetics.

Enthalpy good, entropy bad? What can we learn from protein-ligand binding thermodynamic signatures?

251st National Meeting (2016)

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