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.
Export Options
About this article
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 |
Call for Papers in Thematic Issues
Artificial Intelligence Methods for Biomedical, Biochemical and Bioinformatics Problems
Recently, a large number of technologies based on artificial intelligence have been developed and applied to solve a diverse range of problems in the areas of biomedical, biochemical and bioinformatics problems. By utilizing powerful computing resources and massive amounts of data, methods based on artificial intelligence can significantly improve the ...read more
Eco-friendly Agents for Biological Control of Pathogenic Diseases
The discovery of an alternative biological approach to disease management includes work on medicinal products derived from natural sources as a starting point for the development of eco-friendly agents for these diseases and the injuries they cause, as well as reducing human contact with hazardous chemicals and their residues. We ...read more
Emerging trends in diseases mechanisms, noble drug targets and therapeutic strategies: focus on immunological and inflammatory disorders
Recently infectious and inflammatory diseases have been a key concern worldwide due to tremendous morbidity and mortality world Wide. Recent, nCOVID-9 pandemic is a good example for the emerging infectious disease outbreak. The world is facing many emerging and re-emerging diseases out breaks at present however, there is huge lack ...read more
Exploring Spectral Graph Theory in Combinatorial Chemistry
Scope of the Thematic Issue: Combinatorial chemistry involves the synthesis and analysis of a large number of diverse compounds simultaneously. Traditional methods rely on brute force experimentation, which can be time-consuming and resource-intensive. Spectral Graph Theory, a branch of mathematics dealing with the properties of graphs in relation to the ...read more
- Author Guidelines
- Graphical Abstracts
- Fabricating and Stating False Information
- Research Misconduct
- Post Publication Discussions and Corrections
- Publishing Ethics and Rectitude
- Increase Visibility of Your Article
- Archiving Policies
- Peer Review Workflow
- Order Your Article Before Print
- Promote Your Article
- Manuscript Transfer Facility
- Editorial Policies
- Allegations from Whistleblowers
Related Articles
-
Epigenetic Drugs for Multiple Sclerosis
Current Neuropharmacology CD6 as a Cell Surface Receptor and As a Target for Regulating Immune Responses
Current Drug Targets Prostaglandins and Cyclooxygenases in Glial Cells During Brain Inflammation
Current Drug Targets - Inflammation & Allergy Targeted Drug Delivery to Central Nervous System (CNS) for the Treatment of Neurodegenerative Disorders: Trends and Advances
Central Nervous System Agents in Medicinal Chemistry Neuropeptides as Therapeutic Approach to Autoimmune Diseases
Current Pharmaceutical Design A Rational Approach on the Use of Sex Steroids in Multiple Sclerosis
Recent Patents on CNS Drug Discovery (Discontinued) Systemic Immunomodulation of Autoimmune Disease Using MHC-Derived Recombinant TCR Ligands
Current Drug Targets - Inflammation & Allergy The p35 Family of Apoptosis Inhibitors
Current Genomics The Heme Oxygenase System and Type-1 Diabetes
Current Pharmaceutical Design Anti-NMDA Receptor Encephalitis in Psychiatry
Current Psychiatry Reviews Autoantibody Reaction to Myelin Basic Protein by Plasma Parvovirus B19 IgG in MS Patients
Protein & Peptide Letters Berberine: A Plant-derived Alkaloid with Therapeutic Potential to Combat Alzheimer’s disease
Central Nervous System Agents in Medicinal Chemistry Estrogen and Cytokines Production - The Possible Cause of Gender Differences in Neurological Diseases
Current Pharmaceutical Design Cancer Prevention with Promising Natural Products: Mechanisms of Action and Molecular Targets
Anti-Cancer Agents in Medicinal Chemistry The Anti-inflammatory Potential of Selected Plant-derived Compounds in Respiratory Diseases
Current Pharmaceutical Design Metalloproteinases and Metalloproteinase Inhibitors in Age-Related Diseases
Current Pharmaceutical Design Role of the Innate Immune System in Autoimmune Inflammatory Demyelination
Current Medicinal Chemistry A Closer Look to Polyesters: Properties, Synthesis, Characterization, and Particle Drug Delivery Applications
Nanoscience & Nanotechnology-Asia Gastrointestinal Immune System and Brain Dialogue Implicated in Neuroinflammatory and Neurodegenerative Diseases
Current Molecular Medicine The Need for Physiologically Relevant Peroxisome Proliferator-Activated Receptor-gamma (PPAR-γ) Ligands
Endocrine, Metabolic & Immune Disorders - Drug Targets