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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

The two components of virtual screening. The selection of LBVS and/or SBVS is based on the amount and type of information vailable on the target at the beginning of a screening campaign.
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Figure 1: The two components of virtual screening. The selection of LBVS and/or SBVS is based on the amount and type of information vailable on the target at the beginning of a screening campaign.

Mentions: While in silico screening strategies still suffer from obvious limitations, many new hits have been identified after application of these computer tools. In silico techniques usually involve the screening of chemical compound libraries (i.e., in general the compounds are available or can be purchased, although in some cases the compounds can be virtual and will thus have to be synthesized should they be selected by the process). These techniques are used to predict, instead of measuring, the potency of a small molecule on a given bio-molecular target. Depending on the information available at the beginning of a screening campaign (e.g., crystal structure of the target, and/or knowledge of previously determined chemical compounds acting on the desired target) two strategies can be applied: structure-based virtual screening or SBVS (i.e., docking/scoring) [14, 21-23] or ligand-based virtual screening or LBVS [24-35] (Fig. 1). The first steps of SBVS approaches involve docking computations. These consist of placing the small molecules that are present in the (virtual) chemical library into a (known or predicted) binding pocket such that the predictions of a likely pose and of a relative affinity can be established at a later stage. LBVS, on the other hand, make use of previously identified chemical compounds to identify new ligands based on 2D and/or 3D similarity searches, and in this case, the 3D structure of the target is not required. In some projects, it can be rewarding to combine both SBVS and LBVS with other methods, such as NMR (Nuclear Magnetic Resonance), crystallography and site directed mutagenesis. The projects and the first results obtained after initial screening experiments usually guide the selection of an appropriate set of methods to be used.


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)

The two components of virtual screening. The selection of LBVS and/or SBVS is based on the amount and type of information vailable on the target at the beginning of a screening campaign.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 1: The two components of virtual screening. The selection of LBVS and/or SBVS is based on the amount and type of information vailable on the target at the beginning of a screening campaign.
Mentions: While in silico screening strategies still suffer from obvious limitations, many new hits have been identified after application of these computer tools. In silico techniques usually involve the screening of chemical compound libraries (i.e., in general the compounds are available or can be purchased, although in some cases the compounds can be virtual and will thus have to be synthesized should they be selected by the process). These techniques are used to predict, instead of measuring, the potency of a small molecule on a given bio-molecular target. Depending on the information available at the beginning of a screening campaign (e.g., crystal structure of the target, and/or knowledge of previously determined chemical compounds acting on the desired target) two strategies can be applied: structure-based virtual screening or SBVS (i.e., docking/scoring) [14, 21-23] or ligand-based virtual screening or LBVS [24-35] (Fig. 1). The first steps of SBVS approaches involve docking computations. These consist of placing the small molecules that are present in the (virtual) chemical library into a (known or predicted) binding pocket such that the predictions of a likely pose and of a relative affinity can be established at a later stage. LBVS, on the other hand, make use of previously identified chemical compounds to identify new ligands based on 2D and/or 3D similarity searches, and in this case, the 3D structure of the target is not required. In some projects, it can be rewarding to combine both SBVS and LBVS with other methods, such as NMR (Nuclear Magnetic Resonance), crystallography and site directed mutagenesis. The projects and the first results obtained after initial screening experiments usually guide the selection of an appropriate set of methods to be used.

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