Receptor pseudoreceptor

Yak/Prgen and COMPASS work fundamentally with the surface of molecules, and derive representations of the predicted binding surface of the receptor ( pseudoreceptor ). APOLLO appears to work with features —groups on the molecule that meet specific topological criteria (i.e., which match a specified subgraph isomorphism query) these features must be defined by the user. 

Holtje and Sippl selected a representative training set of twelve superimposed structures. The aforementioned Y AK process resulted in a pseudoreceptor that consists of six amino acid residues (Figure 5). In this pseudoreceptor model, the imidazole ring of the ligands is bound to a tyrosine residue that donates a proton to the imidazole and an asparagine residue that accepts a proton from the imidazole. Hence, two distinct H-bond have been found, which explain the strict binding mode of the imidazole. It has to be noted that the position of these receptor residues relative towards the imidazole is a consequence of... 

If individually positioned residues are in close contact, the program evaluates the possibility of peptide-bond formation and thus links single residues to a peptide. Furthermore, ligand-independent extension (i.e. residues without direct contact to vectors) of the pseudoreceptor can be used in order to complete the peptidic receptor site (e.g. entirely closed shell around the ligand molecules). 

Internal ligand relaxation allows the removal of strain possibly imposed on the ligands by the receptor during correlation-coupled refinement but usually yields suboptimal models. Therefore, correlation-coupled receptor minimization followed by unconstrained ligand relaxation is repeated several times until a highly correlated pseudoreceptor model is obtained in the relaxed state (designated ligand equilibration). 

The pseudoreceptor modeling concept was utilized for (i) reconstruction of experimentally determined receptor sites, (ii) exploration of crucial ligand-receptor interaction sites and (iii) prediction of pharmacological activities of molecules, sometimes compared with results derived from other 3D-QSAR techniques. 

Although the orientations and calculated free binding energies of the sulfonamide ligands are not presented in the original paper, reconstruction of the receptor site via a pseudoreceptor approach was promising and stimulated further activities. 

Fig. 5.6 Part of the pseudoreceptor model for histamine H3-receptor antagonists [25] (one leucine beside the isoleucine residue is omitted for clarity). Hydrogen bonds from ligands to complementary functions of asparagine (Asn), tyrosine (Tyr) and aspartate (Asp) are located in the GR/D-...

Pseudoreceptor Modeling The Construction of Three-Dimensional Receptor Surrogates. 

For many protein drug targets crystal or solution structures are not available. In such cases homology models (130,131)and pseudoreceptor models (132) are often used. However, unless there is a very high conservation of receptor site residues the use of homology models for virtual screening is much riskier than using solved structures. On the other hand, the PDB contains a wealth of protein... 

Vedani A, Zbinden P, Snyder JP, Greenidge PA. Pseudoreceptor modeling the construction of three-dimensional receptor surrogates. J Am Chem Soc 1995 1174987-4994. 

Zbinden P, Dobler M, Folkers G, Vedani A. PrGen pseudoreceptor modeling using receptor-mediated ligand alignment and pharmacophore equilibration. QSAR 1998 17 122-130. 

Further additions to the 3D-QSAR arsenal include comparative molecular similarity indices analysis (CoMSIA) [15], 4D-QSAR [16], COMPASS [17], receptor surface models [18], the pseudoreceptor approach [19], ComPharm [20], and comparative molecular surface analysis (CoMSA) [21], 3-D-invariant, alignment-free descriptor systems such as comparative molecular moment analysis (CoMMA) [22], EVA [23], WHIM [24], and ALMOND [25], have also become available. A survey of the 3D-QSAR literature reveals 1154 entries in the Chemical Abstracts Plus database of these, 79% are journal publications, 19% are conference proceedings, and four are patents related to, or using, 3D-QSAR models. As the number of potential targets amenable to drug discovery is increasing exponentially, it is likely that 3D-QSAR models and methodologies will continue to be developed in the next decade. 

The next step is to translate this interaction field into a model of the receptor which is composed from single isolated amino acids with chemical properties that satisfy the different types of binding present in the pharmacophore. The relative three-dimensional positions of the amino acid binding sites are defined by the corresponding GRIN/GRID results. The resulting amino acid receptor model is sometimes called a pseudoreceptor. ... 

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