Renin modeling

Figure L Stereoview of the inhibitor-bound renin model (cyan) [14]. The inhibitor is displayed as a CPK model (yellow).

Figure 2. Stereoview of a renin inhibitor, Smo-Phe-Atm-ACDMH (yellow), bound in the renin model binding site (green, catalytic aspartic acids in red).

Figure 6. Stereoview of the bound conformation of a phenyl tethered analog (upper, black lines) and a naphthyl tethered analog (lower, black lines) overlaid with Smo-Phe-Ets-ACDMH (gray lines) extracted from the endothiapepsin X-ray crystal structure [17] and oriented in the renin model active site.

Lunney, E. A., and Humblet, C. C. Comparative molecular modeling analyses of endothiapepsin complexes as renin model templates. In Peptides Chemistry, Structure and Biology, Proceedings of the Eleventh American Peptide Symposium, Marshall, G. R., and Rivier, J. E. (Eds.). ESCOM Leiden, Netherlands 387-389 (1990)... 

In animal models, renin inhibitors after iv adrninistration have been shown to be equally efficacious as compared to ACE inhibitors in lowering blood pressure, and to have similar effects on the cardiovascular and renal parameters. Some of the renin inhibitors tested are enalkiren (A-64662), CGP 38 560A, CP 71362, KRI-1230, U-71039, ES6864, and PD-134672. The stmctures of enalkiren and the formula for PD-134672 are shown in Figure 4. 

Bader M, Peters J, Baltatu O et al (2001)Tissue renin-angiotensin systems new insights from experimental animal models in hypertension research. J Mol Med 79 76-102... 

The carboxyl proteases are so called because they have two catalytically essential aspartate residues. They were formerly called acid proteases because most of them are active at low pH. The best-known member of the family is pepsin, which has the distinction of being the first enzyme to be named (in 1825, by T. Schwann). Other members are chymosin (rennin) cathepsin D Rhizopus-pepsin (from Rhizopus chinensis) penicillinopepsin (from Penicillium janthinel-lum) the enzyme from Endothia parasitica and renin, which is involved in the regulation of blood pressure. These constitute a homologous family, and all have an Mr of about 35 000. The aspartyl proteases have been thrown into prominence by the discovery of a retroviral subfamily, including one from HIV that is the target of therapy for AIDS. These are homodimers of subunits of about 100 residues.156,157 All the aspartyl proteases contain the two essential aspartyl residues. Their reaction mechanism is the most obscure of all the proteases, and there are no simple chemical models for guidance. 

For a series of renin inhibitors a good correlation between the measured membrane permeability and log D was found (r2 = 0.8). The model has been validated against a human perfusion model [10], as well as being extended by including molecular weight as a third parameter [27]. A further development of the model is to chronically cannulate the animals so that they can be allowed to recover [28]. This model should avoid any effects from the anesthetic on the absorption process. 

C. Hutchins, and J. Greer, Comparative modeling of proteins in the design of novel renin... 

If the main-chain hydrogen bonding of substrates is conserved among aspartic proteinases, how are the differences in specificities achieved Table 1 defines the enzyme residues that line the specificity pockets for both mouse and human renin. In modeling exercises (e.g., Reference 4) it was assumed that specificities derive from differences in the sizes of the residues in the specificity pockets (Sn) and their ability to complement the corresponding side chains at positions Pn in the substrate/inhibitor. A detailed analysis now shows that this simple assumption only partly accounts for the steric basis of specificity. 

For example, in the specificity subsite S3 the phenyl rings of Phe P3 occupy almost identical positions in both renin inhibitor complexes. Modeling studies have predicted the specificity subsite S3 to be larger in renins than in other aspartic proteinases [4] due to substitution of smaller residues, Pro 111, Leul 14, and Alai 15, in place of larger ones in mammalian and fungal proteinases. However, a compensatory movement of a helix (hN2) makes the pocket quite compact and complementary to the aromatic ring as shown in Figure 5. Thus, the positions of an element of secondary structure differ between renin and other aspartic proteinases with a consequent important difference in the specificity pocket. 

Protease 3D structural models renin-inhibitor complex and drug design... 

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