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Thermodynamics as a Tool for the Optimization of Drug Binding, Thermodynamics - Interaction Studies - Solids, Liquids and Gases

AuthorsMatesanz, Ruth ; Pera, Benet ; Díaz, José Fernando
Issue DateNov-2011
CitationThermodynamics – Interaction Studies – Solids, Liquids and Gases Cap. 28:777-796(2011)
AbstractA non-covalent interaction is a kind of chemical bond, typically between macromolecules, that involves dispersed variations of electromagnetic interactions (Alberts et al. 1994; Connors & Mecozzi 2010). Non-covalent interactions are individually weak as compared with covalent bonds, but their net strength is higher than the sum of that of the individual interactions. There are few drugs that bind irreversibly to their targets, in pharmacology, most drugs establish non-covalent interactions with their target molecules (usually proteins). From a chemical point of view, the affinity constant (Ka) is a very useful measurement for the study of binding reactions as it provides much information about the mechanism. In many cases some chemical or physical properties of ligand or target change with the interaction between them, these changes might help to measure binding constants. It is important to establish the stoichiometry of the complex to be sure that the constants are accurately calculated. From the affinity constants measured it is possible to calculate the standard thermodynamic quantities for the binding reaction: free-energy (ΔG), enthalpy (ΔH) and entropy (ΔS). Our group has already demonstrated that, in some cases, binding affinity measurements are very helpful for the optimization of ligand binding as it can be determined the contribution of every single chemical modification of the ligand to the binding affinity (Buey et al. 2004; Matesanz et al. 2008) One of the objectives of drug development is the search of new or modified compounds with improved properties such as better potency, higher selectivity, better pharmacokinetics or superior drug resistance profiles. An important goal in this objective is the optimization of drugs binding affinity towards their targets, as binding affinity is directly related to potency (Ruben et al. 2006). Moreover, it has been shown that extremely high affinity drugs reflect as well changes in other properties like selectivity (Ohtaka et al. 2004; Ohtaka & Freire 2005) or resistance overcoming ability (Matesanz et al. 2008). Examples of the importance of ligand affinity in drug optimization can be observed in the development of HIV-1 protease inhibitors and statins (cholesterol lowering drugs) over the years as remarked in (Freire 2008). In this chapter we will study the nature of non-covalent interations and the concept of binding constant for these interactions. Examples of methodologies to measure binding constants of small ligands to macromolecules will be introduced and we will emphasize the
need to determine the stoichiometry of the studied system to calculate accurately the constants. Once the thermodynamic concepts were introduced, we will show the use of these kind of studies for the optimization of drug binding to its target. We will detail the role of single chemical modifications in the molecule of study to modulate its binding affinity, and the way to quantify these changes. We will finally further discuss how the selection of the best sustituents can result in the optimization of bindin
Description20 páginas, 5 figuras, 2 tablas -- PAGS nros. 777-796
Publisher version (URL)http:dx.doi.org/10.5772/823
Appears in Collections:(CIB) Artículos
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