Steric model

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. 

Schachman, H. K., 1990. Can a. simple model account for die allo.steric tran.sition of aspartate traiiscarbamoyla.se Journal of Biological Chemistry 263 18583-18586. Te.sts of the po.stnlates of die allo.steric models through experiments on a.spartate tran.scarbamoyla.se. 

The dependence of the j3-deuterium effect on the spatial orientation of the isotopic bond with respect to the developing -orbital, on the a-carbon atom was elegantly demonstrated by Shiner and Humphrey (1963). This work will not be discussed in detail here suffice it to say the suggestion is made that j8-deuterium effects are better correlated by the postulate of hyperconjugation and its angular dependence than by the simple steric model (Shiner and Humphrey, 1963). 

Figure 7. Steric model proposed by Jerina, et al. for the catalytic binding site of cytochrome P-450c (P-448) to account for the stereoselective metabolism of polycyclic aromatic hydrocarbons (48). The boundary should be enlarged in the directions shown to accommodate substrates whose mechanism of stereoselective oxygenation does not fit the steric model originally proposed.

In complexes of crown ethers [303] to [305] (types IV and V) both large groups are located in the larger of the two non-equivalent chiral cavities (Kyba et al., 1978). This was concluded from H nmr spectra of the diastereomeric complexes of [303] with a-phenylethylammonium salts. In the spectra the position of the methyl protons in both diastereomeric complexes is the same, in contrast to the methyl protons in complexes of [284] or [285] with the same salt. In the latter the upheld shift of the methyl protons in the more stable SS-(R) enantiomeric complex differs from that in the less stable SS-(S) enantiomer. Taking into account the available data summarized above, the tentative conclusion seems to be that the simple steric model (see structure... 

An understanding of enzyme action requires not only a knowledge of pathway and rates, but also an explanation of specificity. The dominant idea in this area was that of Emil Fischer, who described the enzyme-substrate complex in terms of lock and key (Fischer, 1894). In essence, Fischer presented a steric model where a cavity in the enzyme was assumed to be shaped to fit the substrate and to hold it firmly in place. This model served enzymologists well for decades and helped them to visualize the interactions between specific... 

The importance of ring contractions, fragmentations, and rearrangements in these types of reactions was again emphasised, and inferences were drawn from this work as to the mechanism of the reaction, based on steric modelling of the compounds. (See Sect. 4.3). 

This statement is actually (and intentionally) not applicable to parts of Chapter 3 where I have made no concessions to the reader who refuses to inspect steric models in conjunction with study of the text. 

Vibert, P.J., Craig, R., and Lehman, W. (1997). Steric-model for activation of muscle thin filaments. J. Molec. Biol. 266, 8-14. 

While the development of the Taft parameter is similar to that of Hammett and Hansch, / )-val ucs are based on rate constants instead of equilibrium constants. The Taft parameter is a measure of changes in activation energy, not standard free energy. Of the Hammett, Hansch, and Taft parameters, the Taft parameter is utilized the least in QSAR studies. Other steric parameters have been developed over time, and like the Taft parameter, all have shortcomings. One alternative steric parameter was developed by Marvin Charton of Pratt Institute in New York. Charton s parameter is based on the van der Waal radius of a substituent.6 Another alternative steric model is the STERIMOL parameter set developed by Arie Verloop of Philips-Duphar in Holland.7 Unlike Taft and Charton, Verloop... 

An active-site model has been proposed to explain the high asymmetric oxidation of sulfide to sulfoxides75 (Fig. 6). The model consists of three pockets, A, B, and C, where pocket B, defined by the two chlorine atoms and the phenylsulfonyl group, is responsible for the high enantioselectivity exhibited for the oxidation of sulfides Rl-S-Rs. The absolute stereochemistry of the final sulfoxides is predicted in terms of a simple steric model, which involves minimization of nonbonded interaction between the RL and Rs groups of the sulfides (RL-S-Rs) and the active site surface of the oxaziridine in an orientative planar transition state. 

The pent-l-en-5-yl radical does not cyclize in any of the matrices. Non-terminal addition would involve very severe steric factors and necessitate the formation of a cyclobutyl structure which would be highly strained. Addition to the terminal end to form the cyclopentyl radical might be expected to occur but steric models again show that approach in the plane of the 77-orbital is impossible and that only approach in the nodal plane can occur. 

The simple steric model for the transition state may be used to predict the absolute configuration of the product. The related reagent (+)-B-Chlorodiisopinocampheylborane reduces ketones with greater ease and efficiency (eq 12). ... 

Figure 3 A, steric model of the active site of cytochrome P450-IA1 based on the metabolism of benzo[a]pyrene the binding site is asymmetrically positioned toward the activated iron-bound oxygen species. (From Jerina et al 1985.) expanded model of A in order to accommodate also non-bay-region or K-region epoxides. (From Kadlubar and Hammons, 1987 Yang, 1988.) C, proposed model in which some flexibility in the angle of oxygen addition to the substrate is allowed. (From Kadlubar and Hammons, 1987.)...

Testa, B. and Purcell, W.P. (1978). A QSAR Study of Sulfonamide Binding to Carbonic Anhy-drase as Test of Steric Models. EurJ.Med.Chem., 13,509-514. 

TBS-protection, a second, boron-mediated, syn aldol reaction led to the formation of 277 with 95% ds. In this case, ketone 278 controlled the stereochemical outcome of the reaction, and chiral ligands on boron were not required. A simple steric model accounts for this selectivity (see Scheme 9-11), and a titanium-mediated aldol reaction would be expected to give the same product. Following elaboration, including an Ireland-Claisen rearrangement, aldehyde 279 was prepared. 

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