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. 2008:2:29-37.
doi: 10.2174/1874091X00802010029. Epub 2008 Mar 10.

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

Olivier Sperandio  1 , Maria A Miteva, Kenneth Segers, Gerry A F Nicolaes, Bruno O Villoutreix
Affiliations

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

Olivier Sperandio et al. Open Biochem J. 2008.

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.

Keywords: Virtual screening; drug discovery; protein-membrane interaction; protein-protein interaction; structure-based drug design.

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Figures

Fig. (1)
Fig. (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.
Fig. (2)
Fig. (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
Fig. (3)
Fig. (3)
Examples of “drug-like” protein-protein antagonists.
Fig. (4)
Fig. (4)
Detected cavities (green) with the computer tool PASS [66], on Factor Va (left) and the PX-domain (right).
Fig. (5)
Fig. (5)
The two known conformations of the discoidin C2 domain of coagulation factor Va, open (magenta) and closed (blue).
Fig. (6)
Fig. (6)
Example of one small molecule identified in the FV-membrane study that impedes protein-membrane interaction, it can be used as a mechanistic probe to investigate this molecular event or, could be used as a starting point to develop anticoagulant molecules.
See this image and copyright information in PMC

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