Pseudoreceptor models

It has not yet been clarified whether the ring substituents interact directly with the binding site or affect the molecular characteristics of the DHP molecules in common. A recently used atomistic pseudoreceptor model for a series of DHP indicated a putative charge-transfer interaction was stabilizing the DHP-binding site complex [19]. To prove this hypothesis qualitative and quantitative analysis of the molecular orbitals of nine DHP derivatives (Fig. 9.11) was performed [18]. Charge-transfer (or electron-donor-acceptor) interactions are indicative of electronic... 

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... 

Figure 5. Pseudoreceptor model for histamine H, agonists by Holtje and Sippl [25]. Four ligands are shown inside the binding region.

This chapter does not cover these classical approaches but rather focuses on basic principles, evolution and scientific applications based on specialized pseudoreceptor modeling software packages. 

In order to build up an atomistic pseudoreceptor model, the following basic steps have to be carried out ... 

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). 

Fig. 5.2 Flowchart of a typical PrCen pseudoreceptor model construction and validation approach.

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. 

The pseudoreceptor model was constructed with six amino acid residues. The imidazole ring of the ligands and the terminal basic function were saturated via... 

Fig. 5.5 (a) Binding site of human carbonic anhydrase I (pdb code 2CAB) with a bound zinc ion (sphere). Arrows indicate the directions of the pseudoreceptor model to rotate and shift amino acid residues, (b) Super-... 

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-...

In a reversed type of approach, we used the pseudoreceptor modeling concept not to develop a tool for SAR predictions but to characterize two discrete ion channel modes on a molecular level [28]. For this purpose, a set of 13 well-characterized 1,4-dihydropyridine (DHP) derivatives with experimentally determined dissociation constants (Kf) for the voltage-gated calcium channel (VGCC) in the resting state (rs) and the open/inactivated state (is) were investigated (Table 5.2). 

Selectivity of the resting state pseudoreceptor model was checked with the same ligands via prediction of their binding behavior to the inactivated channel mode. 

For the construction of a pseudoreceptor model of the open/inactivated state, ligand-derived information was considered indicating the left-hand side of DHPs to be essential for binding [28]. 

Since all pseudoreceptor models are composed of the same six amino acid residues - Thr, Phe, Gly, Met, Tyr, Tyr - transition from resting to open/inactivated state could be described by one additional hydrogen-bond donor interaction (Thr) at the left-hand side of DHPs. 

Fig. 5.7 Pseudoreceptor model of the L-type VGCC in the resting state (a) and the opened/inactivated channel mode (b) with one additional threonine (Thr) at the left... 

Chart 19 Alignment proposed by Botta and co-workers in the pseudoreceptor model for taxanes and epothilones [114], represented on paclitaxel (10) and epothilone B (13)... 

By means of AutoDock [134] and Gold software [135], laulimalide, peloruside and paclitaxel were docked in this structure, but only the former two compounds were able to give profitable interactions, mainly because of the overall size of the ligands. Nevertheless, the calculated binding energies for laulimalide and peloruside into the paclitaxel binding site were favorable to interaction, as well as the binding predictions performed with the pseudoreceptor model [133],... 

Schleifer KJ, Tot E, Holtje HD. Pharmacophore and pseudoreceptor modelling of class lb antiarrhythmic and local anaesthetic lidocaine analogues. Pharmazie 1998 53 596-602. 

Pseudoreceptor Modeling The Construction of Three-Dimensional Receptor Surrogates. 

Gurrath M, Muller G, Holtje HD (1998) Pseudoreceptor modelling in drug design Applications of Yak and PrGen. In Kubinyi H, Folkers G, Martin YC (eds) 3D QSAR in Drug Design, vol. 3 Recent Advances. Kluwer, Dordrecht, pp 135-157... 

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... 

Bassoli, A., Drew, M.G.B., Merlini, L., and Morini, G. (2002a). A general pseudoreceptor model for sweet compounds, semi-quantitative prediction of binding affinity for sweet tasting molecules. J. Med. Chem. 45, 4402—1409. 

Schleifer, K. J. Pseudoreceptor model for ryanodine derivatives at calcium release channels. J. Comput.-Aided Mol. Des. 2000,14, 467—475. 

In order to perform computational protein-ligand docking experiments, a 3-D structure of the target protein at atomic resolution must be available. The most reliable sources are crystal and solution structures provided by the Protein Data Bank (PDB) [7] or from in-house efforts. Homology models [27,28] and pseudoreceptor models [29] are an alternative in the absence of experimental structures. It should be cautioned, however, that the quality of the protein structure is crucial for the success of subsequent docking experiments. Even small changes in structure can drastically alter... 

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

In 1988, a new semiautomated method, APOLLO, was developed by Koehler and Snyder, then at Searle in Chicago [12], Like the MNMM method, it relied upon the user to select the features for the pharmacophore. APOLLO s main significance was that it served as a progenitor of a new line of thought the pseudoreceptor modeling methods Yak and Prgen, developed by Snyder, Koehler, and Vedani. 

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

Gurrath M, Muller G, Holtje HD. Pseudoreceptor modelling in drug design applications of Yak and PrGen. Perspect Drug Discov Des 1998 12 135-157. 

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