2011
DOI: 10.1177/1087057111399573
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Leveraging the Contribution of Thermodynamics in Drug Discovery with the Help of Fluorescence-Based Thermal Shift Assays

Abstract: The development of new drugs with better pharmacological and safety properties mandates the optimization of several parameters. Today, potency is often used as the sole biochemical parameter to identify and select new molecules. Surprisingly, thermodynamics, which is at the core of any interaction, is rarely used in drug discovery, even though it has been suggested that the selection of scaffolds according to thermodynamic criteria may be a valuable strategy. This poor integration of thermodynamics in drug dis… Show more

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Cited by 8 publications
(4 citation statements)
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“…While the former is almost universally explained as a hallmark of an already-degraded or denatured protein (see detailed study of a V75H + I155A DHFR mutant by Bershtein et al [34]), the latter can result from a multiplicity of factors. Some authors have associated a decrease of T m with the small molecule binding more strongly to the unfolded protein [2,3,28,41]. Additionally, destabilization has been attributed to phenomena such as the ligands acting to effect covalent modification of the protein, change in ionic strength leading to a depletion of ions that stabilize the protein, or detergent-like denaturation [42].…”
Section: Experimental Setup and Data Interpretationmentioning
confidence: 99%
“…While the former is almost universally explained as a hallmark of an already-degraded or denatured protein (see detailed study of a V75H + I155A DHFR mutant by Bershtein et al [34]), the latter can result from a multiplicity of factors. Some authors have associated a decrease of T m with the small molecule binding more strongly to the unfolded protein [2,3,28,41]. Additionally, destabilization has been attributed to phenomena such as the ligands acting to effect covalent modification of the protein, change in ionic strength leading to a depletion of ions that stabilize the protein, or detergent-like denaturation [42].…”
Section: Experimental Setup and Data Interpretationmentioning
confidence: 99%
“…The desire to characterise all human proteins and identify those that lead to diseases such as Alzheimer's and Parkinson's, as well as novel drugs that target them, is driving the need for low-volume and high throughput assays that can accurately measure protein stability, ligand binding affinity and kinetics of protein unfolding or aggregation1234567.…”
mentioning
confidence: 99%
“…When ∆G is paired with T m , one can extract the enthalpy of unfolding (∆H) and the entropy of unfolding (∆S). These parameters are related to each other-(−RTlnK) = ∆G = ∆H − T∆S-where R is the gas constant, K is the equilibrium constant, and T is the absolute temperature [43]. All of these parameters are often used in the context of methods like DSC and DSF, and there are several papers in regard to thermodynamic properties and their relationship to each other, which is outside the scope of this review paper [44][45][46][47][48].…”
Section: Stability Parametersmentioning
confidence: 99%