Enthalpy screen of drug candidates

Abstract

The enthalpic and entropic contributions to the binding affinity of drug candidates have been acknowledged to be important determinants of the quality of a drug molecule. These quantities, usually summarized in the thermodynamic signature, provide a rapid assessment of the forces that drive the binding of a ligand. Having access to the thermodynamic signature in the early stages of the drug discovery process will provide critical information towards the selection of the best drug candidates for development. In this paper, the Enthalpy Screen technique is presented. The enthalpy screen allows fast and accurate determination of the binding enthalpy for hundreds of ligands. As such, it appears to be ideally suited to aid in the ranking of the hundreds of hits that are usually identified after standard high throughput screening.

A procedure combining molecular docking and semiempirical method PM7 for identification of selective Shp2 inhibitors

“…Although enzyme/inhibitor complex formation is governed by the Gibbs free energy for the complex formation, the good performance of the theoretical approach employed in this work is in accordance with results from the literature that show that enthalpy is generally the most important factor in determining selectivity since a large favorable binding enthalpy is likely a result of specific intermolecular interactions that are less likely to be present on many targets . The advantage of this approach is the avoidance of the laborious calculation of the entropy of the complex formation.…”

“…Although the ligand‐protein affinity is influenced both by enthalpy and entropy terms, when the focus is on selectivity, enthalpy generally plays the most important role. Ligands whose binding is primarily enthalpy‐driven tend to be more selective for that target because a large favorable binding enthalpy is likely a result of specific intermolecular interactions that are less likely to be present on many targets . Hence, arguably, ligand screening strategies that search for more selective agents could be focused in finding compounds with the most favorable binding enthalpy values.…”

Determination of the binding mechanism of histone deacetylase inhibitors

“…If the binding enthalpy is determined at different temperatures, also the heat capacity, ΔC p , can be calculated, to complete a set of thermodynamic signature for a particular HDAC–ligand pair. The thermodynamic signature of ligand binding is recognized as decision criterion for the selection of the most promising lead candidates during the drug optimization process (Claveria‐Gimeno, Vega, Abian, & Velazquez‐Campoy, ; Ladbury, Klebe, & Freire, ; Schon & Freire, ). One example is the titration of HDAH from Pseudomonas aeruginosa with a perfluorinated analog of SAHA (PFSAHA) (Meyners, Kramer, Yildiz, & Meyer‐Almes, ) (Figure ) Caution: ITC signals include all sorts of heat changes associated with the addition of the ligand to the protein solution.…”

Ergodic Algorithmic Model (EAM), with Water as Implicit Solvent, in Chemical, Biochemical, and Biological Processes

“…Another experimental method suited to the determinations of the information elements of a thermodynamic system in aqueous solution is calorimetry. Freire [27,28] showed how high affinity and selectivity, two essential properties of drugs, can be achieved by the optimization of enthalpic and entropic contributions to binding (the so-called "Thermodynamic Signatures"). If the calorimetric binding experiments are performed at a different temperature, the complete set of information elements can be obtained by applying the EAM model.…”