Receptor molecular properties

Many biological, physical and chemical properties are clearly functions of the three-dimensional (3D) structure of a molecule. Thus, the understanding of receptor-ligand interactions, molecular properties or chemical reactivity requires not only information on how atoms are connected in a molecule (connection table), but also on their 3D structure. 

Combining molecular properties with potency provides a simple yet powerful overview of a screening dataset and can be used to quickly identify ligand-efficient lead-like compounds. In Fig. 17.5, a set of 429 compounds active against 5-hydroxytryptamine lA receptor are displayed in a PSA-ClogP plot with the size of the circle related to ligand efficiency. One can easily spot the efficient binders in area of favorable properties. 

The ability of morphine to desensitize other neurotransmitter receptors coupled to K+ channels may cause long-term consequences in the activity of neurons. The uncoupling of K+ channel from non-opioid receptors that normally tonically inhibit cell firing could result in an increase in the basal firing of the cells. Changes in the set point of neuronal firing could influence gene expression in the cells and alter the molecular properties of the neurons. 

The final part is devoted to a survey of molecular properties of special interest to the medicinal chemist. The Theory of Atoms in Molecules by R. F.W. Bader et al., presented in Chapter 7, enables the quantitative use of chemical concepts, for example those of the functional group in organic chemistry or molecular similarity in medicinal chemistry, for prediction and understanding of chemical processes. This contribution also discusses possible applications of the theory to QSAR. Another important property that can be derived by use of QC calculations is the molecular electrostatic potential. J.S. Murray and P. Politzer describe the use of this property for description of noncovalent interactions between ligand and receptor, and the design of new compounds with specific features (Chapter 8). In Chapter 9, H.D. and M. Holtje describe the use of QC methods to parameterize force-field parameters, and applications to a pharmacophore search of enzyme inhibitors. The authors also show the use of QC methods for investigation of charge-transfer complexes. 

The biosynthesis, molecular properties and receptors for the major colony-stimulating factors, as well as their role in haematopoiesis, is described in Chapter 2. The following section describes the role of G- and GM-CSF in the modulation of the function of mature, circulating neutrophils. 

ALIS measures the MS response of the ligand following its dissociation from the protein-ligand complex. Therefore, the magnitude of the MS response corresponds to the equilibrium concentration of the receptor-ligand complex concentration [ S] times the compound s MS calibration factor Cms, which depends on the ionization efficiency and other molecular properties of the ligand ... 

It is tempting to speculate that the next comprehensive examination of hemopexin-mediated heme transport will have exciting new sections devoted to the molecular properties of MHBP and the hemopexin receptor, to the mechanism of heme release from hemopexin, to new intracellular heme transport partners, and to the links provided by the hemopexin system among heme, iron, and copper at the cellular level. 

Pagliara, A., Testa, B., Carrupt, P.A., Jolliet, P., Morin, C., Morin, D., Urien, S., Tillement, J.P. and Rihoux, J.P. (1998) Molecular properties and pharmacokinetic behavior of cetirizine, a zwitterionic Hl-receptor antagonist. Journal of Medicinal Chemistry, 41, 853-863. 

The molecular properties of G proteins and their subunits, as well as the structural basis of the interactions among the a, p, and y subunits of G proteins and between these subunits and the associated receptor, has been immensely facilitated by X-ray crystallographic... 

It is not yet possible to design a molecule with specific odor (or taste) characteristics because the relations between sensory properties of flavor compounds and their molecular properties are not well understood. As a consequence, the development of compounds with desired flavor qualities has had to rely on relatively tedious synthetic approaches. Recent advances, however, in computer-based methods developed by the pharmaceutical industry to study QSAR (quantitative structure-activity relationships) may ultimately be helpful in the rational design of new flavor-structures with predictable sensory attributes. Results from QSAR studies may also provide insight into the mechanism of the molecule-receptor interaction. 

Varying the side groups X in 27b affects both the stability and selectivity of the complexes (lateral discrimination), and allows the receptor-substrate interactions in biological systems to be modelled, for instance, the interaction between nicotinamide and tryptophan [2.109b]. One may attach to 27b amino acid residues (leading to parallel peptides [2.109] as in 27c), nucleic acid bases or nucleosides, saccharides, etc. The structural features of 27 and its remarkable binding properties make it an attractive unit for the construction of macropolycyclic multisite receptors, molecular catalysts, and carriers for membrane transport. Such extensions require sepa-... 

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