Receptor binding conformational flexibility

SAR studies on melatonin analogues showed that methoxy and amido moieties are important for binding to melatonin receptors various substituents on the 2nd position of the indole ring enhance the binding affinity [52-54]. The conformational flexibility of the C-3 ethylamido side chain is probably responsible for the broad spectrum of biological activities. As a powerful antioxidant melatonin was shown to have significantly broader actions including oncostatic effects [55], immune system stimulation [56], and antiinflammatory functions [57,58]. 

Bradbury, S.P., Mekenyan, O.G., and Ankley, G.T, Quantitative structure-activity relationships for polychlorinated hydroxybiphenyl estrogen receptor binding affinity an assessment of conformer flexibility, Environ. Toxicol. Chem., 15, 1945-1954, 1996. 

Conformational Flexibility and Solvation on Receptor-Ligand Binding Free Energies. 

The fact that receptor binding is a 3-D event would suggest that 3-D descriptors are best able to model biological activity however, there are significant problems inherent in the use of such descriptors. These problems relate to representation of the conformational space available to molecules— for example, the method used to generate the 3-D structures and the way in which conformational flexibility is handled. However, despite these difficulties... 

Pharmacophore keys are 3-D structural keys that are based on features of a molecule that are thought to have relevance for receptor binding. The features typically include hydrogen bond donors, hydrogen bond acceptors, charged centers, aromatic ring centers and hydrophobic centers. Pharmacophore keys are usually based on combinations of three or four pharmacophoric features and their associated distances. Flexibility can be taken into account by combining the keys for all distinct conformations of a molecule. 

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