Receptor binding site models

As with many 3D-QSAR approaches, one first identifies a pharmaco-phoric pattern in the ligands and superimposes them. This step requires that one makes a number of assumptions about the types of interaction that govern 

Calculation of the Ligand-Receptor Interaction Energy and Regression Analysis 

The interaction energy (IE) between ligand and pseudoreceptor is given 

A final word of caution is especially necessary with receptor binding site methods. The models are so explicit in representing part of the macromolecule in atomic detail that it is tempting to believe that they represent the truth. In fact, like all 3D-QSAR models, they represent merely a hypothesis waiting to be disproved by the next experiment. Because of the subjective decisions made in the manual application of this approach, it is not clear how many different models of equivalent statistical quality would be found for any particular data set. 

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Figure 6. Receptor binding site model proposed by Humber (6,1).

RBSM Receptor Binding Site Model SMF Substructural Molecular... 

Embodied in Eq. [7] are two key assumptions. First, the interaction energy between a ligand and receptor can be partitioned into the individual interaction energies between an atom or a group of atoms of the molecule with the complementary receptor atoms. Second, as in Eq. [5] for explicit receptor binding site models, the lower the internal energy of the molecule required to attain the receptor-bound conformation, the higher will be the potency. 

Figure 5.27 Schematic representation of a model for the conformational change of hemagglutinin that at low pH brings the fusion peptide to the same end of the molecule as the receptor binding site. The fusion peptide (purple) is at the end of heUx A about 100 A away from the receptor binding site in the high pH form. In the low pH fragment this region of helix A has moved about 100 A towards the area where the receptor binding sites are expected to be in the intact hemagglutinin molecule. (Adapted from D. Stuart, Nature 371 19-20, 1994.)...

In addition to the deductions one might make about a receptor binding site on the basis of receptor binding data from conformationally constrained ligands as previously described, models of bradykinin and bradykinin antagonists bound to their respective sites on the receptor as complimentary aspects of the overall strategy are also valuable. Unfortunately, due to the nature of the bradykinin... 

The canyons are depressions approximately 15 to 20 A deep that encircle each icosahedral five-fold axis (Figure 1). When first seen in HRV 14, these canyons were postulated to be the site at which a cellular receptor would bind. Subsequent electron-microscopic data revealed that ICAM-1 does indeed bind in the canyon as predicted, although in a somewhat different orientation than early models [22,23]. These canyons allow the receptor binding sites to escape immunological surveillance because the canyons are too narrow to allow an immunoglobulin to contact the canyon floor. Directly underneath the floor of the canyon lies a second important structure, the VP1 hydrophobic pocket. 

Anstead, G.M., Carlson, K.E. and Katzenellenbogen, J.A. (1997) The estradiol pharmacophore ligand structure-estrogen receptor binding affinity relationships and a model for the receptor binding site. Steroids,... 

Computational techniques have allowed investigators to use this extensive amount of biochemical and biophysical information to develop the available structural information, including the inactive structure of rhodopsin (T eller et al., 2001), the GDP-bound Gt heterotrimer (Lambright et al., 1994), and NMR structures of the C-termini of Gat and Gy (Kisselev and Downs, 2003 Kisselev et al., 1998), into molecular models of the receptor-G protein complex (Ciarkowski et al., 2005 Fotiadis et al., 2004 Slusarz and Ciarkowski, 2004). Since the C-terminus of Ga, a critical receptor-binding site, is absent in both structures of G protein heterotrimers (Lambright... 

Perret, P., Laube, B., Schemm, R., Betz, H., Goeldner, M. and Foucaud, B. (2002). Affinity labeling of cysteine-mutants evidences contact residues in modeled receptor binding sites. J. 

Marshall, G.R., Binding-site modeling of unknown receptors. In 3D QSAR in Drug Design, Theory Methods and Applications, Kubinyi, H. (ed.). ESCOM, Leiden, 1993, pp. 80-116. 

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