Low molecular weight inhibitors of Protein-Protein Interactions (PPI's) have been identified for a number of different systems indicating the viability of the computer-aided drug design approaches. However, pathways undertaken by researchers in pharmaceutical companies or in academic
laboratories are not always clearly defined and the protocols that allow the identification of lead compounds often remain blurry. We will enumerate in this review the main approaches carried out to identify and validate PPI's inhibitors. Emphasis will be placed, in a first part, on issues
of particular significance to PPI's such as the problem of identification and validation of interacting sites and on the methods that allow assessing the 3D structure of a targeted complex. On the second part of this review, we will define approaches that allow a rapid identification
of hits capable of inhibiting PPI's. We will highlight the problem of the scoring functions and demonstrate that the majority of the functions available to researchers are not especially relevant for PPI's. We will define why consensus scoring can be an alternative and we will propose
GFscore, a non linear ranked-by number consensus scoring function as a solution to this problem. We will finally discuss the actual challenges that still remain, particularly the problem of the treatment of the receptor flexibility and of the water molecules at the interface of the Protein-Protein
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Document Type: Research Article
Centre National de la Recherche Scientifique, Institut de Biologie Structurale et Microbiologie, Laboratoire Interactions et Modulateurs de Reponses (CNRS FRE 3083), 31 Chemin Joseph Aiguier, 13402 Marseille Cedex 20, France.
Publication date: December 1, 2009
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Combinatorial Chemistry & High Throughput Screening publishes full length original research articles and reviews describing various topics in combinatorial chemistry (e.g. small molecules, peptide, nucleic acid or phage display libraries) and/or high throughput screening (e.g. developmental, practical or theoretical). Ancillary subjects of key importance, such as robotics and informatics, will also be covered by the journal. In these respective subject areas, Combinatorial Chemistry & High Throughput Screening is intended to function as the most comprehensive and up-to-date medium available. The journal should be of value to individuals engaged in the process of drug discoveryand development, in the settings of industry, academia or government.
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