Model receptor sites

Ghose, A. K., Crippen, G. M. The distance geometry approach to modeling receptor sites In Comprehensive Medicinal Chemistry. The Rational Design, Mechanistic Study and Therapeutic Application of Chemical Compounds, Hansch, C.,... 

Ghose, A.K. and Crippen, G.M. (1990). The Distance Geometry Approach to Modeling Receptor Sites. In Quantitative Drug Design. Vol. 4 (Ramsden, C.A., ed.), Pergamon Press, Oxford (UK), pp. 715-733. 

As already mentioned, no structure of a pharmacologically relevant receptor has so far been determined to atomic resolution. However, for the rational design of new biologically active ligands, information about the structures of these receptors is required. So far, various approaches have been developed for modeling receptor sites on the basis of structure/activity relationships [51]. If typical interaction patterns between small molecule ligands and macromolecular receptors were available, they... 

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... 

Receptor models are powerful tools for source apportionment of particulates because a vast amount of particulate species characterization data have been collected at many sampling sites worldwide, and because many aerosol species are primary pollutants. Most of the information available is for elemental concentrations, eg, lead, nickel, and alurninum, although more recent measurements have provided data on concentrations of ionic species and carbonaceous compounds. At a sampling (or receptor) site, the aerosol mass concentration of each species i is... 

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. 

The SBDD approach affected computational chemists positively. The increased number of 3D structures of therapeutically relevant targets opened new opportunities for molecular modeling of the receptor sites. Computational chemists assisted the medicinal chemists in interpreting the fruits of crystallography for design of new ligands. 

Neurokinin-1 Receptor. A homology model of the neurokinin-1 (NKi) receptor was built from the X-ray structure of rhodopsin, using the MOBILE (modeling binding sites including ligand information explicitly) approach. In this procedure, a preliminary model is generated, which is afterwards refined... 

After initial experiments demonstrating that the antiserum was capable of completely inhibiting the binding of [ H]PbTx-3 to its receptor site in rat brain membranes (Figure 9), we began studies designed to evaluate potential of the antiserum for prophylaxis and treatment of brevetoxin intoxication (34). The tethered rat model was used, and surgical implantations were identical to those described above. Heart rate, core and peripheral body temperatures, lead VIO ECG, and arterial blood pressure were monitored continuously. Respiratory rate was recorded each 5 min for the first 3 hr, then each 15 min until 6 hr. 

Fig. 3.4 Three models for prospective function(s) for OBPs during perireceptor delivery of a signal molecule odourant <=> protein <=> receptor site interactions could involve multiple roles. Ligand , OBP , combination(s) buffer and/or carrier and/or transducer from Pelosi, 1994).

One model of an ionic mechanism of action of Li+ in affective disorders has been proposed, in which the receptors for Li+ are ion channels and cation coenzyme receptor sites, and in which the presence of intracellular Li+ in excitable cells results in the displacement of exogenous Na+ and/or other intracellular cations [13]. It has been suggested that this could lead to a decrease in the release of neurotransmitters alternatively it may be that this intracellular Li+ is altering a preexisting, disease-related electrolyte imbalance [14]. A number of observations of such imbalances in affective disorders have been made depression is associated with elevated levels of intracellular Na+ [15] retention of Li+ is observed in manic-depressive patients prior to an episode of mania [ 16] and Na+/K+ activity is defective during both mania and depression [17]. 

---