Allosteric sites, inhibitor selectivity

Fig. 8. Allosteric sites in the mGluR 7TM. The chemical structures of the allosteric inhibitors MPEP, EM-TBPC, BAY36-7620, and CPCCOEt, and the allosteric potentiator Ro 67-7476 are given. The crucial residues or regions for the subtype selectivity of each of the compounds are stated and shown in a schematic illustration of the mGluRl 7TM viewed from the extracellular side of the cell membrane. The residues in mGluRl corresponding to those involved in MPEP binding to mGluR5 are also shown in the illustration.

The fullerene derivatives result to be noncompetitive inhibitors, meaning that, although the catalytic site of AChE could bind cationic fullerenes, the binding of C60 derivatives should take place in allosteric sites (Pastorin et al., 2006). Considering all these actions, with important biomedical applications, the question about selectivity naturally arises, but no answer has been proposed as yet. 

For each of the selected target proteins, a set of 10 pharmacophore models was generated based on receptor-inhibitor complexes from the PDB. The three allosteric sites of hepatitis C virus (HCV) polymerase were represented by three, five, and two models, respectively. Structure-based pharmacophore model generation was performed with the software LIGANDSCOUT using the default settings and... 

Another solution to the inherent selectivity problem could be to target allosteric sites at the PTP protein surface. So far allosteric inhibitors have only been reported for PTPIB [34]. In their paper, Wiesmann and colleagues determined the crystal structure of the complex between PTPIB and 3-(3,5-dibromo-4-hydroxybenzoyl)-... 

Some compounds extend from a purine site into an adjacent hydrophobic region, which is not thought to be used by natural ligands and is often known as the selectivity pocket (Figure 4.3). This is an allosteric site, because it is not used by substrates of the enzyme. The selectivity pocket is so named because it is not well conserved and inhibitor selectivity often correlates with the identity of a gatekeeper residue at the entrance to the pocket, occurring 3 residues before the main-chain NH donor in the purine site. Most compounds that use... 

It is difficult to deconvolute how kinase inhibitor binding mode has implications in the clinic. In general, selectivity tends to increase in the order (i) purine site, (ii) selectivity pocket, and (iii) allosteric site. The ability to overcome resistance mutations in cancer therapy tends to be inversely related to this selectivity pattern. Accordingly, allosteric kinase inhibition may become a preferred mechanism for clinical indications other than cancer. 

The design of bifunctional acetylcholinesterase inhibitors was achieved in order to obtain potent and selective derivatives. Bis-tetrahydroaminacrine showed a simultaneous interaction with the active site and the peripheral site (allosteric site) of the enzyme resulting in an improvement of potency and selectivity. ... 

Burke JR, Pattoli MA, Gregor KR, Brassil PJ, MacMaster JF, McIntyre KW, Yang X, lotzova VS, Clarke W, Stmad J, Qiu Y, Zusi FC (2003) Mechanisms of signal transduction BMS-345541 Is a highly selective inhibitor of IkB kinase that binds at an allosteric site of the enzyme and blocks NF-KB-dependent transcription in mice. J Biol Chem 278 1450-1456. doi 10.1074/jbc. M209677200... 

Substances that do not target the active site but display inhibition by allosteric mechanisms are associated with a lower risk of unwanted interference with related cellular enzymes. Allosteric inhibition of the viral polymerase is employed in the case of HIV-1 nonnucleosidic RT inhibitors (NNRTl, see chapter by Zimmermann et al., this volume) bind outside the RT active site and act by blocking a conformational change of the enzyme essential for catalysis. A potential disadvantage of targeting regions distant from the active site is that these may be subject to a lower selective pressure for sequence conservation than the active site itself, which can lower the threshold for escape of the virus by mutation. 

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