Abstract
Low molecular weight inhibitors of Protein-Protein Interactions (PPIs) 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 PPIs inhibitors. Emphasis will be placed, in a first part, on issues of particular significance to PPIs 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 PPIs. 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 PPIs. 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 complexes.
Keywords: Drug design, virtual screening, docking, protein interaction, inhibitor, NMR, mapping
Combinatorial Chemistry & High Throughput Screening
Title: Protein-Protein Interaction Inhibition (2P2I): Fewer and Fewer Undruggable Targets
Volume: 12 Issue: 10
Author(s): Stephane Betzi, Francoise Guerlesquin and Xavier Morelli
Affiliation:
Keywords: Drug design, virtual screening, docking, protein interaction, inhibitor, NMR, mapping
Abstract: Low molecular weight inhibitors of Protein-Protein Interactions (PPIs) 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 PPIs inhibitors. Emphasis will be placed, in a first part, on issues of particular significance to PPIs 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 PPIs. 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 PPIs. 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 complexes.
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Cite this article as:
Betzi Stephane, Guerlesquin Francoise and Morelli Xavier, Protein-Protein Interaction Inhibition (2P2I): Fewer and Fewer Undruggable Targets, Combinatorial Chemistry & High Throughput Screening 2009; 12 (10) . https://dx.doi.org/10.2174/138620709789824736
DOI https://dx.doi.org/10.2174/138620709789824736 |
Print ISSN 1386-2073 |
Publisher Name Bentham Science Publisher |
Online ISSN 1875-5402 |
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