ArticleProceedings of the National Academy of Sciences of the United States of America2007
Protein protein interaction inhibition (2P2I) combining high throughput and virtual screening: Application to the HIV-1 Nef protein.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2007. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 45 papers.
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Who cites it
45 citing papers in PubMed, 115 citations in OpenAlex.
- Neuro-HIV-New insights into pathogenesis and emerging therapeutic targets.FASEB journal : official publication of the Federation of American Societies for Experimental Biology · 2023Article
- Targeted protein degradation as an antiviral approach.Antiviral research · 2023Article
- Review
- Methods for the Discovery and Identification of Small Molecules Targeting Oxidative Stress-Related Protein-Protein Interactions: An Update.Antioxidants (Basel, Switzerland) · 2022Review
- Improving Docking Power for Short Peptides Using Random Forest.Journal of chemical information and modeling · 2021Article
- Synergy and allostery in ligand binding by HIV-1 Nef.The Biochemical journal · 2021Article
- Identification of potential antivirals against SARS-CoV-2 using virtual screening method.Informatics in medicine unlocked · 2021Article
- Direct interaction between ABCA1 and HIV-1 Nef: Molecular modeling and virtual screening for inhibitors.Computational and structural biotechnology journal · 2021Article
- Lovastatin Inhibits HIV-1-Induced MHC-I Downregulation by Targeting Nef-AP-1 Complex Formation: A New Strategy to Boost Immune Eradication of HIV-1 Infected Cells.Frontiers in immunology · 2019Article
- Evolution of In Silico Strategies for Protein-Protein Interaction Drug Discovery.Molecules (Basel, Switzerland) · 2018Review
- In silico structure-based approaches to discover protein-protein interaction-targeting drugs.Methods (San Diego, Calif.) · 2017Review
- How order and disorder within paramyxoviral nucleoproteins and phosphoproteins orchestrate the molecular interplay of transcription and replication.Cellular and molecular life sciences : CMLS · 2017Review
- Herb-target interaction network analysis helps to disclose molecular mechanism of traditional Chinese medicine.Scientific reports · 2016Article
- Discovery of newMolecular diversity · 2015Article
- Structural Disorder within Paramyxoviral Nucleoproteins and Phosphoproteins in Their Free and Bound Forms: From Predictions to Experimental Assessment.International journal of molecular sciences · 2015Article
- Surfing the Protein-Protein Interaction Surface Using Docking Methods: Application to the Design of PPI Inhibitors.Molecules (Basel, Switzerland) · 2015Review
- Hierarchical virtual screening approaches in small molecule drug discovery.Methods (San Diego, Calif.) · 2015Review
- Development and validation of a high-content bimolecular fluorescence complementation assay for small-molecule inhibitors of HIV-1 Nef dimerization.Journal of biomolecular screening · 2014Article
- Druggable orthosteric and allosteric hot spots to target protein-protein interactions.Current pharmaceutical design · 2014Review
- Small molecule inhibitors of the HIV-1 virulence factor, Nef.Drug discovery today. Technologies · 2013Review
Corrections and comments
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Authors and funding
8 authors at 6 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Protein-protein recognition is the cornerstone of multiple cellular and pathological functions. Therefore, protein-protein interaction inhibition (2P2I) is endowed with great therapeutic potential despite the initial belief that 2P2I was refractory to small-molecule intervention. Improved knowledge of complex molecular binding surfaces has recently stimulated renewed interest for 2P2I, especially after identification of "hot spots" and first inhibitory compounds. However, the combination of target complexity and lack of starting compound has thwarted experimental results and created intellectual barriers. Here we combined virtual and experimental screening when no previously known inhibitors can be used as starting point in a structure-based research program that targets an SH3 binding surface of the HIV type I Nef protein. High-throughput docking and application of a pharmacophoric filter on one hand and search for analogy on the other hand identified drug-like compounds that were further confirmed to bind Nef in the micromolar range (isothermal titration calorimetry), to target the Nef SH3 binding surface (NMR experiments), and to efficiently compete for Nef-SH3 interactions (cell-based assay, GST pull-down). Initial identification of these compounds by virtual screening was validated by screening of the very same library of compounds in the cell-based assay, demonstrating that a significant enrichment factor was attained by the in silico screening. To our knowledge, our results identify the first set of drug-like compounds that functionally target the HIV-1 Nef SH3 binding surface and provide the basis for a powerful discovery process that should help to speed up 2P2I strategies and open avenues for new class of antiviral molecules.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.