Pseudo-receptor

Although ADMET-QSAR methodologies are traditionally not considered RD methods, a pseudo-receptor may be needed to extract relevant ADMET descrip-... 

Vedani A, Zbinden P, Snyder JP. Pseudo-receptor modeling a new concept for the three-dimensional construction of receptor binding sites. J Recept Res 1993 13 163-177. 

Traversa U, Bombi G, Camaioni E, Macchiarulo A, Costantino G, Palmieri C, CaciagU F, PeUicciari R (2003) Rat brain guanosine binding site. Biological studies and pseudo-receptor construction. Bioorg Med Chem 11 5417-5425... 

These equations have highlighted the steric, physicochemical, and electronic requirements at the specified grid locations of the compounds and the pseudo receptor [216]. 

C. Importance of the B. Pseudo-receptor models screening of compound... 

CHAPTER 28 Pharmacophore Identification and Pseudo-Receptor Modeling... 

The resulting hypothetical receptor model is named minireceptor or pseudo-receptor and can be used to derive three-dimensional quantitative structure-activity relationships (3D-QSAR). The concept was originally developed in the 1980s by several groups. ... 

FIGURE 28.6 Molecular structures of the two most active inducers identified by the pseudo-receptor. 

The pseudo-receptor concept has been applied in recent years to analyze crucial ligand-receptor interaction sites and to establish 3D-QS ARs for the prediction of biological activities of ligands. A variety of application studies have shown that the pseudo-receptor concept is a versatile tool to establish 3D-QSAR models, often better in their predictive behavior compared to results obtained from classical 3D-QSAR approaches (e.g. CoMFA). Several application studies have been published which have shown the value but also the limitations of this approach. ... 

In a recently published study by Bohacec et al. the pseudo-receptor concept was successfully applied to identify novel small molecule inducers of fetal hemoglobin. Four available active compounds (Figure 28.5) were selected, based on activity and diversity, for the construction of an initial pharmacophore. 

When working with pseudo-receptors, and in general with quantitative structure-activity relationships (QSAR) of any dimension, a word of caution is necessary with respect to the biological data that is used. These should preferably constitute binding affinities from a single laboratory, a prerequisite which is also true for all QSAR studies. Since the receptor models simulate interaction events (AH) in a highly simplihed manner, the experimental data which are combined with them in a correlation analysis mnst be as close to the molecular level as possible. It is therefore nonsense to correlate the calculated interaction energies... 

Bohacek, R., Boosalis, M. S., McMartin, C., Pallet, D. V., Perrine, S. P. Identification of novel small-molecule inducers of fetal hemoglobin using pharmacophore and PSEUDO receptor models. Chem. Biol. Drug Des. 2006, 67, 318—328. 

The design of new pharmaceuticals depends in many cases on a detailed knowledge of the receptor pocket into which the drug binds. Structural data on receptors is seldom available, so a program was developed to computationally generate an artificial protein receptor, denoted as a "pseudo-receptor". 

The method uses decision algorithms to pick the residues to mutate such that a close fit around the substrate of interest is achieved. Energy minimization and molecular dynamics calculations are used to optimize the fit of the pseudo-receptor about the substrate. An example problem is described using a hepta-peptide from the carboxyl terminal of CCK, as well as a benzodiazepine molecule which acts on the same receptor, as the substrates of interest. 

In this paper we develop a new method for finding the three-dimensional space that surrounds a substrate/ligand. This space, which is the chemical equivalent of the receptor, is represented as a protein structure, referred herein as a "pseudo-receptor". A variety of computational tools are used to create the pseudo-receptor. A molecular mechanics and dynamics program, CHARMm(l), is used to calculate the energy and conformational features of the pseudo-receptor. The program QUANTA(l) is used to define the preliminary protein sequence, secondary structure, graphically examine molecular interactions, interface with CHARMm, and model amino-acid mutations in the protein sequence. 

The enthalpic and entropy contributions to the binding and stability of the pseudo-receptor and substrates will be described in more detail elsewhere. However, it is important to note that one must obtain the net free energy of the binding... 

Figure 4. Configuration of sidechains of mutated pseudo-receptor with CCK7. Residues of the pseudo-receptor which have not been mutated have been removed for viewing clarity.

An extension to the pseudo-receptor approach is to utilize the thermodynamic perturbation method (8) to calculate approximate values for the free energy of binding of various... 

A second consequence of the pseudo-receptor approach to drug design is to consider the pseudo-receptor as the drug molecule of interest. This protein could then be synthesized and used to experimentally test for binding to selected substrates and to subsequently be used as the drug itself. This problem would require additional structural modification to stabilize the protein structure in the form found to best bind the model substrate. Complete hydration models of the pseudo-receptor with substrate can be used to test for solvent stability in these studies. 

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