Macromolecule receptors

Ligand means here a small molecule that binds to a specific site (or sites) on a receptor macromolecule. The term drug... 

In this variant of insurmountable antagonism, the antagonist acts by combining with a separate inhibitory site on the receptor macromolecule. Agonist and antagonist molecules can be bound at... 

Based on these rather extensive and not entirely realistic assumptions, the fraction of the receptors in the AR state is given by Eq. (1.32) however, only some of these agonist-combined, isomerized, receptor macromolecules are free of antagonist and thus able to initiate a response. To... 

FIGURE 1.28 An extension to two ligands, A and B, of the scheme for the constitutive activity shown in Figure 1.11, which is reproduced as the front face of the cube. We suppose that A and B combine with separate sites on the receptor macromolecule, R, so that both can be present at the same time (top edge of the rear face of the cube). Active and inactive states of the receptor are represented by the right- and left-hand side faces respectively. 

Here, the model is formally similar to the one discussed in Appendix 1.6B, which describes the application of the law of mass action to a scheme (Figure 1.28) in which each receptor macromolecule carries a separate binding site for each of two ligands. However, in the mechanism for the action of a G-protein-coupled receptor illustrated in Figure 1.14, only two (R G and LR G) of the eight possible conditions of the receptor are active. The diagram below reproduces Figure 1.14 with the addition of the 12 equilibrium constants ... 

Step 2 involves knowing what properties turn a macromolecule into a receptor. All receptors may be macromolecules, but all macromolecules are certainly not receptors. Receptor macromolecules are frequently proteins or glycoproteins. Certain properties must be present if a macromolecule is going to have what it takes to be a druggable target. The receptor macromolecule must be intimately connected with the disease in question, but not integral to the normal biochemistry of a wide range of processes. 

Section 3.1 has outlined traditional methods of drug design which are largely independent of knowledge concerning the structure of the receptor itself, or the receptor macromolecule. 

Crystal structures solved by X-ray or neutron diffraction provide a static picture of the receptor macromolecule, and of uncomplexed and liganded... 

Thus, any foreign compound, which comes into contact with a biological system, will cause certain perturbations in that system. These biological responses, such as the inhibition of enzymes and interaction with receptors, macromolecules, or organelles, may not necessarily be toxicologically relevant. This point is particularly important when assessing in vitro data, and it involves the concept of a dose threshold or the lack of such a threshold, in the "one molecule, one hit" theory of toxicity. 

DISCO considers three-dimensional conformations of compounds not as coordinates but as sets of interpoint distances, an approach similar to a distance geometry conformational search. Points are calculated between the coordinates of heavy atoms labeled with interaction functions such as HBD, HBA or hydrophobes. One atom can carry more than one label. The atom types are considered as far as they determine which interaction type the respective atom would be engaged in. The points of the hypothetical locations of the interaction counterparts in the receptor macromolecule also participate in the distance matrix. These are calculated from the idealized projections of the lone pairs of participating heavy atoms or H-bond forming hydrogens. The hydrophobic points are handled in a way that the hydrophobic matches are limited to, e.g., only one atom in a hydrophobic chain and there is a differentiation between aliphatic and aromatic hydrophobes. A minimum constraint on pharmacophore point of a certain type can be set, e.g. if a certain feature is known to be required for activity [53, 54]. 

Receptor-mediated endocytosis is the selective uptake of extracellular macromolecules (such as cholesterol) through their binding to specific cell-surface receptors. The receptor-macromolecule complex then accumulates in clathrin-coated pits and is endocytosed via a clathrin-coated vesicle. 

In addition to exploring the nature and properties of useful drug molecules, investigating the structure and function of the other half of the pharmacodynamic equation, the receptor macromolecule, is important. Knowledge of the structure of the receptor macromolecule now permits research scientists to design lead compounds from scratch that are probabilistically well suited for further development and optimization. 

In this circumstance the medicinal chemist must resort to an indirect approach to study the molecular architecture of receptors. This approach, receptor mapping ( >), comprises a detailed analysis of the molecular architecture of specific high-affinity, chiral ligands which can undergo minimal, or no conformational change. The results of such analyses can then be interpreted in terms of complementary topographical features of the recognition site on the receptor macromolecule. 

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