Molecular modelling receptor binding

The biological properties of dioxin include an ability to bind to a protein known as the AH (aromatic hydrocarbon) receptor Dioxin IS not a hydrocarbon but it shares a certain structural property with aromatic hydrocarbons Try constructing molecular models of dioxin and anthracene to see these similarities... 

The compound shown is diethylstilbestrol (DES) it has a number of therapeutic uses in estrogen replacement therapy DES is not a steroid but can adopt a shape that allows it to mimic estrogens such as estradiol (p 1100) and bind to the same receptor sites Construct molecular models of DES and estradiol that illustrate this similanty in molecular size shape and location of polar groups... 

Fig. 2. Molecular modeling of dopamine D2 receptor agonists used to define the molecular conformation needed for selective high affinity binding.

A widely used 3-D QSAR method that makes use of PLS is comparative molecular field analysis (CoMFA), in which a probe atom is used to calculate the steric and electronic fields at numerous points in a 3D lattice within which the molecules have been aligned. Poso et al. [56] used the technique to model the binding of coumarins to cytochrome P450 2A5, with similar results to those obtained by Bravi and Wikel [55]. Shi et al. [57] used it to model the estrogen receptor binding of a large diverse set of compounds, and Cavalli et al. [58] used it to develop a pharmacophore for hERG potassium... 

Another crucial problem for any neurochemical model is cause and effect. Neuroleptics have a high affinity for dopamine receptors, particularly the D2-subtype. There is also a highly significant positive correlation (r > +0.9) between this receptor binding and their clinical potency (Seeman, 1980). But, this does not necessarily implicate elevated dopamine levels as the cause of schizophrenia. Moreover, blockade of dopamine receptors happens very rapidly, whereas clinical benefits are only seen after chronic treatment. Rose (1973) has criticised the reductionist statement that an abnormal biochemistry causes schizophrenia because it relates cause and effect at different organisational levels (namely, the molecular and behavioural). But, while it can be legitimate to discuss cause and effect at the same level that chlorpromazine blocks dopamine receptors (one molecule altering the response of another), it is not valid to infer that increased dopamine activity causes schizophrenia. Put another way ... 

Malherbe, P. N. K., Knoflach, F Zenner, M. T et al. (2003) Mutational analysis and molecular modeling of the allosteric binding site of a novel, selective, non-competitive antagonist of the metabotropic glutamate 1 receptor. J. Biol. Chem. 278,8340-8347. 

---