Topographical models

Murphy, P.N.C., Ogilvie, J., Arp, P.A. 2009. Topographic modelling of soil moisture conditions a comparison and verification of two models. European Journal of Soil Science, 60, 94-109. 

Fig. 7.4. A simple topographical model showing the absolute configuration of the acetates reacting faster with cholesterol esterase and lipase (modified from [19]). S = smaller group ...

Several observations of this type that have been published may appear confusing at first but have led to the design of useful topographical models... 

To rationalize the stereospecificity of PLE toward a large variety of monocarboxylic and dicarboxylic esters, Tamm and co-workers have proposed the general formula displayed in Fig. 7.5 [5 5] [67]. Here, no representation of the active site is implied, but the model does rationalize numerous data and allows some qualitative predictions. A qualitative topographical model of the active site of PLE has been proposed by Jones and co-workers [68] [69], As shown in Fig. 7.6, substrate binding is defined by a carboxylate group that interacts with the catalytic serine residue, and by one or two hydrophobic groups that bind to sites 1 and/or 2. 

Perhaps the most elaborate and successful topographical model of PLE currently available is that also conceived by Jones and co-workers and shown... 

Fig. 7.6. Topographical model of the active site of pig liver esterase showing the catalytic OH group and two binding sites (1 and 2) capable of accommodating hydrophobic groups of the substrate. Binding to site 1 is stronger and, thus, dominates until the steric dimensions of the site are exceeded. The model shows two substrates in position, namely dimethyl 3-methylglu-tarate (top) and dimethyl 3-benzylglutarate (bottom), which are hydrolyzed preferentially to the (R)- and (5)-monoester, respectively [68].

Fig. 7.7. Topographical model of the active site of pig liver esterase as proposed by Jones and co-workers [70] [71]. The model postulates two hydrophobic sites, one large (HL) and one small (Hs), and two polar binding sites, one in the front (PF) and one in the back (PB). The serine sphere shows the approximate zone of action of the catalytic OH group, a) A view from the top with the dimensions in A the sites HL, Hs, and PF are at ground level and have an elevation of 3.1 A, 2.3 A, and 1.6 A, respectively, while PB is located 1.5 A above ground level and has an elevation of 0.8 A. b) A computer-generated perspective view with dimethyl phenylmalonate positioned to have its pro-S ester group close to the catalytic site [72a].

Topographical models such as those discussed above are valuable attempts to deduce an indirect and simplified picture of enzymatic sites from the steric properties of substrates. A direct approach has also become practical, namely the determination by X-ray crystallography of the three-dimensional structure of hydrolase-ligand complexes [74],... 

Figure 13.5 Topographical interaction model of ana adrenergic receptor generated based on public site-directed mutagenesis. Both pharmacophore models have been mapped into the topographical model of the receptor. The model reveals putative receptor interaction sites for most of the pharmacophoric features observed within each antagonist class, (a) Class I pharmacophore with prazosin as reference compound (b) class II pharmacophore with compound 10 as reference. Pharmacophoric features are red for posi-...

Another topographical model, advanced for the renal vascular DA receptor by Erhardt (92) is described in greater detail in another section of this monograph (93). This model locates important receptor sites on Cartesian coordinates. It extends the McDermed model by suggesting a second site of steric hindrance about 2.0 A above the plane of the ethylamine chain and an auxiliary binding site, alluded to previously, opposite the principal site of bulk intolerance. As this model, which is consistent with the structures of most DA receptor agonists, specifically locates the amine and "meta"-0H it can be utilized to rationalize the enantioselectivity of known chiral DA receptor agonists (94). 

A topographical model has been proposed to explain why (E)-2-(3,4-dihydroxyphenyl)cyclopropylamine, 1, and alpha-methyldopamine (AMDA) are inactive in the renal vascular dopamine (DA) receptor system. In this model a steric protrusion (S2) resides approximately lX above the generalized plane of the receptor and acts to impede interaction with molecules such as 1 and AMDA which possess additional bulk in this region. Recent developments in DA structure-activity relationships offer further support for the existence of the S2 site. 

Figure 1. Topographical model of the renal vascular dopamine receptor (12).

Figure 2.1 Topographical model of SLC29A1, the hENTl. Highlighted circles indicate amino acids that have been identified as relevant residues through chimera and mutagenesis studies.

Figure 2.2 Topographical model of SLC28A1, the hCNTl. Highlighted circles indicate amino acids that have been identified as relevant residues through chimera and mutagenesis studies. The red residues are a N-glycosylation sites, the green residues are involved in pyrimidine and purine selectivity, and the yellow residue is a genetic variant whose effect resembles the N4-type nucleoside transporter.

Fossa, P., Menozzi, G. and Mosti, L. (2001) An updated topographical model for phosphodiesterase 4 (PDE4) catalytic site. Quant. Struct. -Act. Relat., 20, 17-22. 

Erhardt, P. W., Hagedom, A A, Sabio, M. (1988). Cardiotonic agents 3—A topographical model of the cardiac c-AMP phosphodiesterase receptor. Molecular Pharmacology, 33, 1—13. 

Erhardt, P. W., Chou, Y-L. (1991). A topographical model for the cAMP phosphodiesterase III active site. Life Sciences, 49, 553-568. 

Two extreme topographic models are important in describing most of the phenomena concerning adsorption on solid surfaces ... 

Topographical models for short and long graft chains underwater. (Reprinted with permission from Uchida, E., and Ikada, Y. Macmmolecules, 30, 5464-5469,1997, copyright (1997) American Chemical Society.)... 

Figure 10.5 False color 2D map showing the interface index distribution across one tablet side. The image is obtained by plotting the relative value of the index at each probed point on the topographic model.

---