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

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          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.

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          Most cited references65

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          Structure of the MDM2 oncoprotein bound to the p53 tumor suppressor transactivation domain.

          The MDM2 oncoprotein is a cellular inhibitor of the p53 tumor suppressor in that it can bind the transactivation domain of p53 and downregulate its ability to activate transcription. In certain cancers, MDM2 amplification is a common event and contributes to the inactivation of p53. The crystal structure of the 109-residue amino-terminal domain of MDM2 bound to a 15-residue transactivation domain peptide of p53 revealed that MDM2 has a deep hydrophobic cleft on which the p53 peptide binds as an amphipathic alpha helix. The interface relies on the steric complementarity between the MDM2 cleft and the hydrophobic face of the p53 alpha helix and, in particular, on a triad of p53 amino acids-Phe19, Trp23, and Leu26-which insert deep into the MDM2 cleft. These same p53 residues are also involved in transactivation, supporting the hypothesis that MDM2 inactivates p53 by concealing its transactivation domain. The structure also suggests that the amphipathic alpha helix may be a common structural motif in the binding of a diverse family of transactivation factors to the TATA-binding protein-associated factors.
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            Online predicted human interaction database.

            High-throughput experiments are being performed at an ever-increasing rate to systematically elucidate protein-protein interaction (PPI) networks for model organisms, while the complexities of higher eukaryotes have prevented these experiments for humans. The Online Predicted Human Interaction Database (OPHID) is a web-based database of predicted interactions between human proteins. It combines the literature-derived human PPI from BIND, HPRD and MINT, with predictions made from Saccharomyces cerevisiae, Caenorhabditis elegans, Drosophila melanogaster and Mus musculus. The 23,889 predicted interactions currently listed in OPHID are evaluated using protein domains, gene co-expression and Gene Ontology terms. OPHID can be queried using single or multiple IDs and results can be visualized using our custom graph visualization program. Freely available to academic users at http://ophid.utoronto.ca, both in tab-delimited and PSI-MI formats. Commercial users, please contact I.J. juris@ai.utoronto.ca http://ophid.utoronto.ca/supplInfo.pdf.
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              A hot spot of binding energy in a hormone-receptor interface.

              The x-ray crystal structure of the complex between human growth hormone (hGH) and the extracellular domian of its first bound receptor (hGHbp) shows that about 30 side chains from each protein make contact. Individual replacement of contact residues in the hGHbp with alanine showed that a central hydrophobic region, dominated by two tryptophan residues, accounts for more than three-quarters of the binding free energy. This "functional epitope" is surrounded by less important contact residues that are generally hydrophilic and partially hydrated, so that the interface resembles a cross section through a globular protein. The functionally important residues on the hGHbp directly contact those on hGH. Thus, only a small and complementary set of contact residues maintains binding affinity, a property that may be general to protein-protein interfaces.
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                Author and article information

                Journal
                Open Biochem J
                TOBIOCJ
                The Open Biochemistry Journal
                Bentham Science Publishers Ltd.
                1874-091X
                10 March 2008
                2008
                : 2
                : 29-37
                Affiliations
                [1 ]Inserm U648, University of Paris 5, 45 rue des Sts Peres, 75006 Paris, France
                [2 ]Department of Biochemistry, Cardiovascular Research Institute Maastricht, Maastricht University, the Netherlands
                Author notes
                [* ]Address correspondence to this author at the Inserm U648, University of Paris 5, 45 rue des Sts Peres, 75006 Paris, France; E-mail: bruno.villoutreix@ 123456univ-paris5.fr
                Article
                TOBIOCJ-2-29
                10.2174/1874091X00802010029
                2570552
                18949072
                468690ea-1cb5-4424-b46f-069a7999a155
                2008 Bentham Science Publishers Ltd.

                This is an open access article distributed under the terms of the Creative Commons Attribution License ( http://creativecommons.org/licenses/by/2.5/), which permits unrestrictive use, distribution, and reproduction in any medium, provided the original work is properly cited.

                History
                : 20 January 2008
                : 8 February 2008
                : 23 February 2008
                Categories
                Article

                Biochemistry
                structure-based drug design,drug discovery,virtual screening,protein-protein interaction,protein-membrane interaction

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