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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 references 81

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      Docking and scoring in virtual screening for drug discovery: methods and applications.

      Computational approaches that 'dock' small molecules into the structures of macromolecular targets and 'score' their potential complementarity to binding sites are widely used in hit identification and lead optimization. Indeed, there are now a number of drugs whose development was heavily influenced by or based on structure-based design and screening strategies, such as HIV protease inhibitors. Nevertheless, there remain significant challenges in the application of these approaches, in particular in relation to current scoring schemes. Here, we review key concepts and specific features of small-molecule-protein docking methods, highlight selected applications and discuss recent advances that aim to address the acknowledged limitations of established approaches.
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        Reaching for high-hanging fruit in drug discovery at protein-protein interfaces.

        Targeting the interfaces between proteins has huge therapeutic potential, but discovering small-molecule drugs that disrupt protein-protein interactions is an enormous challenge. Several recent success stories, however, indicate that protein-protein interfaces might be more tractable than has been thought. These studies discovered small molecules that bind with drug-like potencies to 'hotspots' on the contact surfaces involved in protein-protein interactions. Remarkably, these small molecules bind deeper within the contact surface of the target protein, and bind with much higher efficiencies, than do the contact atoms of the natural protein partner. Some of these small molecules are now making their way through clinical trials, so this high-hanging fruit might not be far out of reach.
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          Anatomy of hot spots in protein interfaces.

          Binding of one protein to another is involved in nearly all biological functions, yet the principles governing the interaction of proteins are not fully understood. To analyze the contributions of individual amino acid residues in protein-protein binding we have compiled a database of 2325 alanine mutants for which the change in free energy of binding upon mutation to alanine has been measured (available at http://motorhead. ucsf.edu/thorn/hotspot). Our analysis shows that at the level of side-chains there is little correlation between buried surface area and free energy of binding. We find that the free energy of binding is not evenly distributed across interfaces; instead, there are hot spots of binding energy made up of a small subset of residues in the dimer interface. These hot spots are enriched in tryptophan, tyrosine and arginine, and are surrounded by energetically less important residues that most likely serve to occlude bulk solvent from the hot spot. Occlusion of solvent is found to be a necessary condition for highly energetic interactions. Copyright 1998 Academic Press.
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            Author and article information

            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
            Journal
            Open Biochem J
            TOBIOCJ
            The Open Biochemistry Journal
            Bentham Science Publishers Ltd.
            1874-091X
            10 March 2008
            2008
            : 2
            : 29-37
            2570552
            TOBIOCJ-2-29
            10.2174/1874091X00802010029
            18949072
            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.

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