that allosteric inhibitors alter the movement or the arrangement of flexible protein domains that are encoded by a single gene, whereas in the case of allosteric interfacial inhibitors peptide synthesis the domains are represented by separately encoded and non covalently linked polypeptides. Allostery has become a prominent biological and pharmacological topic55; however, in some contexts its definition has evolved. For instance, allosteric effects are commonly used to refer to propagated effects that produce conformational changes within a biomolecule. This definition is different from the original one proposed by Changeux, Jacob and Monod55,56 and cannot be readily related to interfacial interactions. Concluding remarks and prospects Targeting complex macromolecular systems is becoming mainstream in drug discovery.
As protein surfaces tend to be relatively shallow, it is thermodynamically difficult to identify or synthesize small molecules that compete with large endogenous ligands. Targeting multicomponent molecular machines using interfacial inhibitors that bind at their interfacial hinges overcomes TGF-beta this difficulty because these inhibitors are thermodynamically more efficient and likely to be more selective than competitive inhibitors, which need to cover a large protein–protein need to be flexible; they must undergo a range of movements around intermolecular hinges to create transient clefts that can be stabilized by the binding of interfacial inhibitors. The ‘jamming’ of the molecular machines, even if reversible, tends to be highly toxic because of the necessary orderly timing and concerted actions of biological systems.
Interestingly, interfacial inhibitors represent a large fraction of the drug market . Quinolones represent one of the largest fraction of the antibiotics market, with annual sales above US$7 billion. In the anti HIV market, the horticulture recently approved integrase inhibitor raltegravir is now routinely used both as a first line therapy and in patients who fail to benefit from the highly active antiretroviral therapy regimen. The market shares for raltegravir amounted to over $1 billion in 2010 and are expected to rease in 2011. The outstanding activity and good tolerance of the two other integrase inhibitors in late stage clinical trials, elvitegravir and dolutegravir, makes it likely that they will be approved in 2012.
In addition, some non nucleoside reverse transcriptase inhibitors may act not only as allosteric inhibitors but also as interfacial inhibitors. In the anticancer drug market, both the camptothecin and noncamptothecin drugs targeting TOP1 act as interfacial inhibitors, similarly to the anticancer drugs targeting TOP2, tubulin and target of rapamycin . Drugs that are clinically approved for treating human diseases are listed in TABLE 1. The objective of this article was to define and elucidate the concept of interfacial inhibition by providing examples and defining its identity with respect to other modes of inhibition. As described above, many allosteric inhibitors are interfacial inhibitors, but the converse is not always true. There are several obvious implications of the interfacial inhibitor paradigm for drug discovery. First, the assays for discovering interfacial inhibitors need to take into account the stabilization .