Receptor fitting mapping

The molecular size and shape descriptors may indicate if a ligand molecule, L, does not fit the active site. Unfortunately, in many cases the receptor site cannot be described in simple terms of large , width , and depth . The MTD (minimal topologic difference) method allows a receptor site mapping in the frame of a series of bioactive compounds. The MVD (minimal volume difference) method is an improved variant of the MTD method, which takes into account the 3D extension of a molecule. These two methods are described here in some detail. The results obtained in the study of anti-carcinogenic activity of some retinoids and in the inhibition of carbonic-anhydrase (CA) by a series of sulfonamides are also presented in this chapter. 

Thus, there has been much interest in preparation of rigid analogues both for their utility in mapping receptors and because it was felt that an intrinsically correct fit would maximize intrinsic potency. 

With one exception (Smith et al, 1996), all the studies of complexes of viruses with other proteins are hybrids of cryo-EM for the complex and crystallography for its components. The fitting of atomic models within cryo-EM density maps has revealed the relative positioning of structural components of viruses, and their receptors or antibodies, and has afforded insights into the mechanisms of cell invasion, viral uncoating, and immune recognition. 

Flg 2 (a) Hypothetical receptor map of the active site of prostaglandin cyclooxygenase, showing points of binding or reactivity with the enzyme substrate, arachidonic acid (b) The anti-inflammatory aryl-acetlc acids - here, Indomethacln - which inhibit this enzyme, can fit the same receptor map in a way which explains their structure-activity relationships (from Ref 13 with permission) ... 

Figure 11.9. Arrangements of the inner (blue) and outer (red) p-sheet parts of the (a) a and (b) non-a subunits (see Figs. 11.4 and 11.6), after fitting to the densities in the 4.6-A map of the receptor. The arrangement of the sheets in the a subunits switches to that of the non-a sheets when ACh binds. The views are in the same direction, toward the central axis from outside the pentamer. Arrows and angles in A denote the sense and magnitudes of the rotations relating the a to the non-a sheets. The traces are aligned so that the inner sheets are superimposed. [Adapted from Unwin et al. (30).l...

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