Enthalpic contributions, ligand binding

Ligand structures can be represented by molecular fields (electrostatic or steric), which contain enthalpic contributions to binding when implemented by conventional comparative molecular field analysis (CoMFA) (see Comparative Molecular Field Analysis (CoMFA)). Steric volume incorporated in molecular shape analysis (MSA) (Figure la) is another representation commonly used in SAR studies (see Molecular Surface and Volume) Alternatively, in the hypothetical active site lattice (HASL) approach, molecules are represented by a three-dimensional grid of points (lattice) associated with discrete electronic properties. ... 

According to the equation (21.2), ligand-receptor interactions are characterized by enthalpy-entropy compensation in which one term favors and the other disfavors binding. While enthalpic contributions include electrostatic, hydrogen bond, and Van der Waals interactions, entropic contributions arise from several sources. On one hand, the loss of flexibility upon binding has an important entropic cost, counterbalanced on the other hand by the displacement of ordered water molecules. This will be discussed in the next section as well as the various types of drug-receptor interactions. 

The primary contribution to the hydrophobic effect comes from the favorable increase in system entropy upon the release of ordered first-shell waters from nonpolar surface areas on both the macromolecule and the ligand upon ligand binding there are also secondary enthalpic contributions. 

Thermodynamic effects on ligand binding affinity can roughly be divided into two classes enthalpic contributions, which can be derived from electrostatic and van der Waals potentials by examining the distances between interacting groups, and entropic contributions, which arise from the dynamics of theses groups. 

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