ArticleChemical science2020
Computational strategy for intrinsically disordered protein ligand design leads to the discovery of p53 transactivation domain I binding compounds that activate the p53 pathway.
Article in Chemical science, 2020. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 29 papers.
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Who cites it
29 citing papers in PubMed, 57 citations in OpenAlex.
- Beyond the structure-function paradigm: A comprehensive review of intrinsically disordered proteins.Biochemistry and biophysics reports · 2026Review
- Targeting the intrinsically disordered AR-NTD through a machine learning-based enhanced sampling workflow.Nature communications · 2026Article
- Fundamentals and emerging frontiers in p53-targeted drug development.Biochemistry and biophysics reports · 2026Review
- Sec8: a novel positive regulator of RIG-I in anti-RNA viral defense.Cell death & disease · 2026Article
- pH Sensitivity of the SERF1a Conformational Ensemble.ACS omega · 2026Article
- New Approach for Targeting Small-Molecule Candidates for Intrinsically Disordered Proteins.Methods and protocols · 2025Article
- Article
- DIRseq: a method for predicting drug-interacting residues of intrinsically disordered proteins from sequences.bioRxiv : the preprint server for biology · 2025Article
- Biological insights from integrative modeling of intrinsically disordered protein systems.Current opinion in structural biology · 2025Review
- Ensemble Docking for Intrinsically Disordered Proteins.Journal of chemical information and modeling · 2025Article
- A Database for Large-Scale Docking and Experimental Results.Journal of chemical information and modeling · 2025Article
- Conformational modulation of intrinsically disordered transactivation domains for cancer therapy.PNAS nexus · 2025Review
- Martini3-IDP: improved Martini 3 force field for disordered proteins.Nature communications · 2025Article
- Advances in nephroprotection: the therapeutic role of selenium, silver, and gold nanoparticles in renal health.International urology and nephrology · 2025Review
- Ensemble docking for intrinsically disordered proteins.bioRxiv : the preprint server for biology · 2025Article
- Exploring chemical space for "druglike" small molecules in the age of AI.Frontiers in molecular biosciences · 2025Review
- IDRdecoder: a machine learning approach for rational drug discovery toward intrinsically disordered regions.Frontiers in bioinformatics · 2025Article
- PBLD enhances antiviral innate immunity by promoting the p53-USP4-MAVS signaling axis.Proceedings of the National Academy of Sciences of the United States of America · 2024Article
- Repurposing of drug molecules from FDA database against Hepatitis C virus E2 protein using ensemble docking approach.Molecular diversity · 2024Article
- Molecular simulations integrated with experiments for probing the interaction dynamics and binding mechanisms of intrinsically disordered proteins.Current opinion in structural biology · 2024Review
Corrections and comments
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Authors and funding
11 authors at 1 institution in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Intrinsically disordered proteins or intrinsically disordered regions (IDPs) have gained much attention in recent years due to their vital roles in biology and prevalence in various human diseases. Although IDPs are perceived as attractive therapeutic targets, rational drug design targeting IDPs remains challenging because of their conformational heterogeneity. Here, we propose a hierarchical computational strategy for IDP drug virtual screening (IDPDVS) and applied it in the discovery of p53 transactivation domain I (TAD1) binding compounds. IDPDVS starts from conformation sampling of the IDP target, then it combines stepwise conformational clustering with druggability evaluation to identify potential ligand binding pockets, followed by multiple docking screening runs and selection of compounds that can bind multi-conformations. p53 is an important tumor suppressor and restoration of its function provides an opportunity to inhibit cancer cell growth. TAD1 locates at the N-terminus of p53 and plays key roles in regulating p53 function. No compounds that directly bind to TAD1 have been reported due to its highly disordered structure. We successfully used IDPDVS to identify two compounds that bind p53 TAD1 and restore wild-type p53 function in cancer cells. Our study demonstrates that IDPDVS is an efficient strategy for IDP drug discovery and p53 TAD1 can be directly targeted by small 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.