Physics at the Biomolecular Interface by Ariel Fernández

Author:Ariel Fernández
Language: eng
Format: epub
Publisher: Springer International Publishing, Cham

Thus, in principle, side effects resulting from off-target ligand binding may be minimized by selectively targeting nonconserved dehydrons unique to the desired target protein with the guidance of a measure of wrapping proximity between structures. In this r egard, this chapter reveals that packing defects may act not only as selectivity filters operative across homolog proteins, but also as selectivity switches, to re-engineer a protein inhibitor to redirect its impact towards another target. This latter role requires taking advantage of the spatial displacement of packing defects across aligned homologous structures.

Functional differences across homolog proteins sharing a common fold are very frequent in biology. Previous studies revealed that the wrapping constitutes a molecular dimension explored when evolution is constrained to preserve the fold for functional reasons. Thus, it is likely that wrapping differences across paralogs are indicative of the functional fine tuning needed to avoid dosage imbalances (see Chap. 6). It is precisely this fine tuning that needs to be discriminated in drug-based molecular therapy. As this chapter reveals, such wrapping differences offer a new control in constructing the selectivity filters and selectivity switches that may endow the wrapping technology with a high therapeutic value.

Structural descriptors of protein binding sites, such as hydrophobicity [25], curvature [26] and accessibility [27] are routinely used t o guide inhibitor design. However, examination of the 814 non-redundant protein-inhibitor PDB complexes reveals that 488 of them have binding cavities with only average hydrophobicity [25], not significantly higher than the rest of the surface. In such cases, ligand affinity is attributed to the intermolecular hydrogen-bonding propensities of the inhibitor, inferred from protein-substrate transition-state mimetics [21–24]. However charge screening in water renders putative intermolecular hydrogen bonds unlikely promoters of protein-ligand association, unless water removal is favored at the interface by some pre-existing feature on the surface of the protein [8].

One obvious such feature is the solvent-exposed nonpolar moiety, except that, as stated above, such features occur infrequently on binding sites and if they do, they are highly conserved across homologs. A more common and less troublesome water-excluding feature has been recently identified. We have reported [3, 8, 18, 28, 29] that dehydrons constitute sticky sites with a propensity to become dehydrated as a result of protein associations.

To explore the potential of dehydrons as promoters of drug selectivity, we start by noting that in most PDB protein-inhibitor complexes, the ligand is in effect a wrapper of protein dehydrons, although it was not purposely designed to fulfill this role. In this way, the available bioinformatics data support the novel design concept. Ultimately, we shall develop a wrapping technology and provide evidence supporting the idea that targeting dehydrons that are not conserved across paralogs constitutes a useful strategy to enhance the selectivity of the inhibitor. Thus, the notion of wrapping (packing) similarity will be rigorously introduced and used selectively to modify a multiple-target inhibitor to achieve a higher specificity towards a particular target and subsequently to redirect its impact towards an alternative target.

Download

Copyright Disclaimer:
This site does not store any files on its server. We only index and link to content provided by other sites. Please contact the content providers to delete copyright contents if any and email us, we'll remove relevant links or contents immediately.