Receptor site conformations

Genetic algorithms can also be used to perform molecular docking [Judson et d. 1994 Jont et d. 1995b Oshiro et d. 1995]. Each chromosome codes not only for the internal conform tion of the ligand as described in Section 9.9.1 but also for the orientation of the ligand withi the receptor site. Both the orientation and the internal conformation will thus vary as th populations evolve. The score of each docked structure within the site acts as the fitnes function used to select the individuals for the next iteration. 

The essential feature of the AAA is a comparison of active and inactive molecules. A commonly accepted hypothesis to explain the lack of activity of inactive molecules that possess the pharmacophoric conformation is that their molecular volume, when presenting the pharmacophore, exceeds the receptor excluded volume. This additional volume apparently is filled by the receptor and is unavailable for ligand binding this volume is termed the receptor essential volume [3]. Following this approach, the density maps for each of the inactive compounds (in their pharm conformations superimposed with that of active compounds) were constructed the difference between the combined inactive compound density maps and the receptor excluded volume represents the receptor essential volume. These receptor-mapping techniques supplied detailed topographical data that allowed a steric model of the D[ receptor site to be proposed. 

For example, the rigid, planar flavone 84 is completely tasteless. Phyllodul-cin (77) and the flavanones 79 and 80, on the other hand, can exist in a conformational equilibrium between a planar form (with the B-ring in the quasiequatorial disposition) and a bent form (with the B-ring assuming a quasiaxial orientation). Fig. 23,i presents the best binding to the receptor site. 

Fig. 31.— The Two Possible Conformations of Aspartame (18) Interacting with the Receptor Site." [Key O, carbon G, oxygen , nitrogen and o, hydrogen.]...

That the sweet and bitter responses are intimately associated is clear from the results of gustatory studies of all of the conformationally defined sugars and of other organic compounds. If a carbohydrate has any taste at all, this is invariably sweet, bitter-sweet, or bitter. Chemical modification may alter the taste of a sweet compound so that the product is bitter-sweet or bitter, and it is now generally agreed that the two basic tastes may each be a feature of a single compound. It appears, therefore, that the interactions of these polyfunctional stimulants involve two different sets of receptor sites, representing sweet and bitter modalities. ... 

Greater insight into the conformational structure of the receptor site(s) is gained by a series of physical measurements. Lefkowitz et al. (39) performed an optically detected magnetic reso-... 

Formation of the BPDE-DNA adduct requires a study of (l) Benzo ring conformations of BPDEs and adducts (2) The rehybridization of amino groups on the benzo for the C10-N bond formation (3) The receptor sites resulting from a conformational adjustment of DNA to accommodate an intercalated and finally an intercalative covalently bound BPDE, and the base sequence specificity in the formation of the receptor site (U) Classical intercalation and the orientation of CIO of the BPDEs toward the reactive N2(G), N6(a), 06(G) and... 

KARMA is an interactive computer assisted drug design tool that incorporates quantitative structure-activity relationships (QSAR), conformational analysis, and three-dimensional graphics. It represents a novel approach to receptor mapping analysis when the x-ray structure of the receptor site is not known, karma utilizes real time interactive three-dimensional color computer graphics combined with numerical computations and symbolic manipulation techniques from the field of artificial intelligence. 

At the cellular level, plant secondary metabolites have five major effects on herbivores (a) alteration of DNA replication, RNA transcription, and protein synthesis (b) alteration of membrane transport processes (c) enzyme inhibition and activation (d) blocking of receptor sites for endogenous chemical transmitters and (e) affecting the conformation of other macromolecules (Robinson, 1979). 

The stereochemistry of the y-isomer is shown in the diagram, and when converted into a conformational stereodrawing it can be seen that there are three axial chlorines and three equatorial ones. Ring flip produces an alternative conformation of equal energy, but it can be seen that this is identical to the first stracture rotation through 180° produces an identical and, therefore, superimposable structure. It can be seen that conformational change will not stop the compound interacting with the insect receptor site. 

Figure 5. Step 2b in the modified MacFarland bioactivity model. Binding, involving the change from a weak to a strong complex. Conformational changes in both substrate and receptor site may take place.

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