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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

Detected cavities (green) with the computer tool PASS [66], on Factor Va (left) and the PX-domain (right).
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Figure 4: Detected cavities (green) with the computer tool PASS [66], on Factor Va (left) and the PX-domain (right).

Mentions: Research in the past decade has revealed that many cytosolic proteins are recruited to different cellular membranes to form protein-protein and lipid-protein interactions during cell signaling and membrane trafficking. Membrane assembly of these peripheral proteins is mediated by a growing number of modular membrane targeting domains, including C1, C2, PH, FYVE, PX, ENTH, ANTH, BAR, FERM, and tubby domains, that recognize specific lipid molecules in the membranes [59]. However, the mechanisms by which these domains and their host proteins are recruited to and interact with various cell membranes are only beginning to be unraveled [59]. Among these protein domains, we analyzed the structure of several protein domains known to be involved in membrane interaction, namely, the discoidin C2 domain of coagulation factor Va [60], plasma beta-2 glycoprotein 1 [61], cyclooxygenase [62], PX domain [63], and the tubby-protein [64]. We found, in agreement with a recent bioinformatics study [65] that these membrane-binding regions possess specific chemical and topological properties such as cationic patches that are surrounded by aromatic and aliphatic clusters capable of interaction with phospholipids head groups. In addition, we noticed that a druggable pocket [19] (Fig. 4) was present at the expected protein-membrane interface region (or nearby) which suggests that inhibition of membrane-binding (possibly stabilization but this needs new investigations) could be addressed via combined in silico-in vitro procedures.


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)

Detected cavities (green) with the computer tool PASS [66], on Factor Va (left) and the PX-domain (right).
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 4: Detected cavities (green) with the computer tool PASS [66], on Factor Va (left) and the PX-domain (right).
Mentions: Research in the past decade has revealed that many cytosolic proteins are recruited to different cellular membranes to form protein-protein and lipid-protein interactions during cell signaling and membrane trafficking. Membrane assembly of these peripheral proteins is mediated by a growing number of modular membrane targeting domains, including C1, C2, PH, FYVE, PX, ENTH, ANTH, BAR, FERM, and tubby domains, that recognize specific lipid molecules in the membranes [59]. However, the mechanisms by which these domains and their host proteins are recruited to and interact with various cell membranes are only beginning to be unraveled [59]. Among these protein domains, we analyzed the structure of several protein domains known to be involved in membrane interaction, namely, the discoidin C2 domain of coagulation factor Va [60], plasma beta-2 glycoprotein 1 [61], cyclooxygenase [62], PX domain [63], and the tubby-protein [64]. We found, in agreement with a recent bioinformatics study [65] that these membrane-binding regions possess specific chemical and topological properties such as cationic patches that are surrounded by aromatic and aliphatic clusters capable of interaction with phospholipids head groups. In addition, we noticed that a druggable pocket [19] (Fig. 4) was present at the expected protein-membrane interface region (or nearby) which suggests that inhibition of membrane-binding (possibly stabilization but this needs new investigations) could be addressed via combined in silico-in vitro procedures.

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