Broad-scale analysis of thermodynamic signatures in medicinal chemistry: are enthalpy-favored binders the better development option?. Issue 4 (April 2019)

• Record Type: Journal Article
• Authors: Klebe, Gerhard
• Is Part Of: Drug discovery today. Volume 24:Issue 4(2019)
• Page Start: 943
• Page End: 948
• Publication Date: 2019-04
• Subjects: Drugs -- Design -- Periodicals; Drugs -- Research -- Periodicals; 615.1
• DOI: 10.1016/j.drudis.2019.01.014
• Languages: English
• ISSNs: 1359-6446

Abstract

Highlights: Thermodynamic signature render ligands with enthalpy-dominated profile as superior. Chagrin followed initial euphoria as thermodynamics were evaluated on incomplete data. Thermodynamics consider binding process from separate ligand and protein to complex. Water displacement or entrapment at binding site significantly impacts signature. ITC is conducted under different conditions hampering comparison on absolute scale. Abstract : Thermodynamic profiles of ligand binding, particularly enthalpically favored binding signatures, have been suggested as a criterion to support the decision-making process around which compounds to select for further optimization in drug development. The concept was enthusiastically taken up, but turned out to be too superficial, either because many aspects determining thermodynamic profiles are insufficiently appreciated or because it is difficult to compare such data on a global scale. The impact of water, changes in protonation states, along with buffer dependencies and incompatible measurement conditions that are far from standard conditions hamper such broad-scale comparisons. However, thermodynamic signatures can make us aware of the impact of these aspects and provide important hints for improving our understanding of the binding process and defining criteria for drug optimization.