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Screening Outside the Catalytic Site: Inhibition of Macromolecular Inter-actions Through Structure-Based Virtual Ligand Screening Experiments.

Sperandio O, Miteva MA, Segers K, Nicolaes GA, Villoutreix BO - Open Biochem J (2008)

Bottom Line: Protein-protein interactions play crucial roles in a number of biological processes, and, as such, their disruption or stabilization is becoming an area of intense activity.Along the same line, inhibition of protein-membrane could be of major importance in several disease indications.Despite the many challenges associated with the development of such classes of interaction modulators, there has been considerable success in the recent years.

View Article: PubMed Central - PubMed

Affiliation: Inserm U648, University of Paris 5, 45 rue des Sts Peres, 75006 Paris, France.

ABSTRACT
During these last 15 years, drug discovery strategies have essentially focused on identifying small molecules able to inhibit catalytic sites. However, other mechanisms could be targeted. Protein-protein interactions play crucial roles in a number of biological processes, and, as such, their disruption or stabilization is becoming an area of intense activity. Along the same line, inhibition of protein-membrane could be of major importance in several disease indications. Despite the many challenges associated with the development of such classes of interaction modulators, there has been considerable success in the recent years. Importantly, through the existence of protein hot-spots and the presence of druggable pockets at the macromolecular interfaces or in their vicinities, it has been possible to find small molecule effectors using a variety of screening techniques, including combined virtual ligand-in vitro screening strategy. Indeed such in silico-in vitro protocols emerge as the method of choice to facilitate our quest of novel drug-like compounds or of mechanistic probes aiming at facilitating the understanding of molecular reactions involved in the Health and Disease process. In this review, we comment recent successes of combined in silico-in vitro screening methods applied to modulating macromolecular interactions with a special emphasis on protein-membrane interactions.

No MeSH data available.


Related in: MedlinePlus

Examples of “drug-like” protein-protein antagonists.
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Figure 3: Examples of “drug-like” protein-protein antagonists.

Mentions: Crude structural analysis of experimental protein-protein complex could initially give the impression that the topological features present within the interface will not favor the efficient and selective binding of a small molecule able to interfere with the formation or the stabilization of a macromolecular complex. Clearly, the interaction surface involved is rather large (700-1500 Å2) and the binding surfaces tend to be relatively flat [36, 38]. However it was suggested that the size of the interaction patch of residues present at the interface is not systematically meant to be covered by the small molecule [39], but rather that the binding of a drug in one specific region of the interface could be enough to perturb complex formation or to the opposite, stabilize an interaction. For example, the subset of the interface that contributes to high-affinity is much smaller [39] than the interface itself and it is not significantly bigger than that of a standard “drug-like” molecule [40-42] (Fig. 3). Consistent with this view, the existence of “hot-spots” have been introduced by Wells and co-workers [40] some 15 years ago. Using alanine scanning mutagenesis experiments on human growth hormone and its receptor, they demonstrated that even though the binding interface is quite large, only a subset of the residues involved is directly implicated in the bulk of the binding energy. Therefore, the perspective of finding small molecules that specifically interact with those hot-spots revived the pursuit of protein-protein interaction antagonists (and possibly agonists). Since, a lot of work has been put through the characterization of the hot-spot regions.


Screening Outside the Catalytic Site: Inhibition of Macromolecular Inter-actions Through Structure-Based Virtual Ligand Screening Experiments.

Sperandio O, Miteva MA, Segers K, Nicolaes GA, Villoutreix BO - Open Biochem J (2008)

Examples of “drug-like” protein-protein antagonists.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2570552&req=5

Figure 3: Examples of “drug-like” protein-protein antagonists.
Mentions: Crude structural analysis of experimental protein-protein complex could initially give the impression that the topological features present within the interface will not favor the efficient and selective binding of a small molecule able to interfere with the formation or the stabilization of a macromolecular complex. Clearly, the interaction surface involved is rather large (700-1500 Å2) and the binding surfaces tend to be relatively flat [36, 38]. However it was suggested that the size of the interaction patch of residues present at the interface is not systematically meant to be covered by the small molecule [39], but rather that the binding of a drug in one specific region of the interface could be enough to perturb complex formation or to the opposite, stabilize an interaction. For example, the subset of the interface that contributes to high-affinity is much smaller [39] than the interface itself and it is not significantly bigger than that of a standard “drug-like” molecule [40-42] (Fig. 3). Consistent with this view, the existence of “hot-spots” have been introduced by Wells and co-workers [40] some 15 years ago. Using alanine scanning mutagenesis experiments on human growth hormone and its receptor, they demonstrated that even though the binding interface is quite large, only a subset of the residues involved is directly implicated in the bulk of the binding energy. Therefore, the perspective of finding small molecules that specifically interact with those hot-spots revived the pursuit of protein-protein interaction antagonists (and possibly agonists). Since, a lot of work has been put through the characterization of the hot-spot regions.

Bottom Line: Protein-protein interactions play crucial roles in a number of biological processes, and, as such, their disruption or stabilization is becoming an area of intense activity.Along the same line, inhibition of protein-membrane could be of major importance in several disease indications.Despite the many challenges associated with the development of such classes of interaction modulators, there has been considerable success in the recent years.

View Article: PubMed Central - PubMed

Affiliation: Inserm U648, University of Paris 5, 45 rue des Sts Peres, 75006 Paris, France.

ABSTRACT
During these last 15 years, drug discovery strategies have essentially focused on identifying small molecules able to inhibit catalytic sites. However, other mechanisms could be targeted. Protein-protein interactions play crucial roles in a number of biological processes, and, as such, their disruption or stabilization is becoming an area of intense activity. Along the same line, inhibition of protein-membrane could be of major importance in several disease indications. Despite the many challenges associated with the development of such classes of interaction modulators, there has been considerable success in the recent years. Importantly, through the existence of protein hot-spots and the presence of druggable pockets at the macromolecular interfaces or in their vicinities, it has been possible to find small molecule effectors using a variety of screening techniques, including combined virtual ligand-in vitro screening strategy. Indeed such in silico-in vitro protocols emerge as the method of choice to facilitate our quest of novel drug-like compounds or of mechanistic probes aiming at facilitating the understanding of molecular reactions involved in the Health and Disease process. In this review, we comment recent successes of combined in silico-in vitro screening methods applied to modulating macromolecular interactions with a special emphasis on protein-membrane interactions.

No MeSH data available.


Related in: MedlinePlus