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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

Five cavities detected by PocketPicker [37] on MDM2. The predicted deepest and largest pocket (blue arrow) is indeed the key binding site for p53 and small molecules impeding p53 binding. Red spheres represent regions that are more buried in the protein interior as opposed to blue spheres, that become fully solvent exposed when the color shift to navy blue
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Figure 2: Five cavities detected by PocketPicker [37] on MDM2. The predicted deepest and largest pocket (blue arrow) is indeed the key binding site for p53 and small molecules impeding p53 binding. Red spheres represent regions that are more buried in the protein interior as opposed to blue spheres, that become fully solvent exposed when the color shift to navy blue

Mentions: Overall, in silico and HTS methods have been very successful in screening catalytic sites, in part because the pocket to be screened is usually “druggable” (e.g., well formed binding region with a topology and physico-chemical properties compatible with the tight binding of a small molecule), although even if druggable, there are usually no easy targets. The situation can be significantly different though when screening protein-protein interfaces. For PPI, and in contrast to conventional druggable targets, the small molecule inhibitors or stabilizers can be thought, at first, as having to interact or interfere with a large interface area, often lacking a well formed cavity or cleft [1]. Because of this preconceived idea, the rational design of small molecules able to perturb PPI has long being thought of as an unreachable goal. However, today, several successful examples have been reported [36] confirming the hypothesis that small non-peptide molecules can interfere with PPIs. Indeed, even at protein-protein interfaces, druggable pockets displaying characteristics closely related to the ones forming catalytic sites can be found (Fig. 2).


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)

Five cavities detected by PocketPicker [37] on MDM2. The predicted deepest and largest pocket (blue arrow) is indeed the key binding site for p53 and small molecules impeding p53 binding. Red spheres represent regions that are more buried in the protein interior as opposed to blue spheres, that become fully solvent exposed when the color shift to navy blue
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 2: Five cavities detected by PocketPicker [37] on MDM2. The predicted deepest and largest pocket (blue arrow) is indeed the key binding site for p53 and small molecules impeding p53 binding. Red spheres represent regions that are more buried in the protein interior as opposed to blue spheres, that become fully solvent exposed when the color shift to navy blue
Mentions: Overall, in silico and HTS methods have been very successful in screening catalytic sites, in part because the pocket to be screened is usually “druggable” (e.g., well formed binding region with a topology and physico-chemical properties compatible with the tight binding of a small molecule), although even if druggable, there are usually no easy targets. The situation can be significantly different though when screening protein-protein interfaces. For PPI, and in contrast to conventional druggable targets, the small molecule inhibitors or stabilizers can be thought, at first, as having to interact or interfere with a large interface area, often lacking a well formed cavity or cleft [1]. Because of this preconceived idea, the rational design of small molecules able to perturb PPI has long being thought of as an unreachable goal. However, today, several successful examples have been reported [36] confirming the hypothesis that small non-peptide molecules can interfere with PPIs. Indeed, even at protein-protein interfaces, druggable pockets displaying characteristics closely related to the ones forming catalytic sites can be found (Fig. 2).

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