ArticleProceedings of the National Academy of Sciences of the United States of America2018
Exploring the structural origins of cryptic sites on proteins.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2018. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 75 papers.
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Who cites it
75 citing papers in PubMed, 139 citations in OpenAlex.
- Fragment-Based Discovery of KLK6 and KLK7 Inhibitors.Journal of chemical information and modeling · 2026Article
- The influence of ligands on AlphaFold3 prediction of cryptic pockets.Communications biology · 2026Article
- Biophysical insights into a cryptic ligand site in the hydrophobic core of human PCNA.Biophysical journal · 2026Article
- Cryptic pockets in proteins: Harnessing conformational dynamics for rational drug design.Acta pharmaceutica Sinica. B · 2026Article
- CryptoBank: A resource for the identification and prediction of cryptic sites in proteins.Science advances · 2026Article
- Assessing the Performance of BioEmu in Understanding Protein Dynamics.International journal of molecular sciences · 2026Article
- AI accelerate the identification of druggable targets by 3D structures of proteins and compounds.NPJ precision oncology · 2026Review
- UniPocket: Unified Ligand and Cryptic Pocket Prediction from Protein Language Model Embeddings.ACM-BCB ... ... : the ... ACM Conference on Bioinformatics, Computational Biology and Biomedicine. ACM Conference on Bioinformatics, Computational Biology and Biomedicine · 2026Article
- In Silico Analysis of CMolecules (Basel, Switzerland) · 2025Article
- SARS-CoV-2 Mpro Dihedral Angles Reveal Allosteric Signaling.Proteins · 2025Article
- CrypToth: Cryptic Pocket Detection through Mixed-Solvent Molecular Dynamics Simulations-Based Topological Data Analysis.Journal of chemical information and modeling · 2025Article
- CrypTothML: An Integrated Mixed-Solvent Molecular Dynamics Simulation and Machine Learning Approach for Cryptic Site Prediction.International journal of molecular sciences · 2025Article
- Deconstruction of Dual-Site Tankyrase Inhibitors Provides Insights into Binding Energetics and Suggests Critical Hotspots for Ligand Optimization.Journal of medicinal chemistry · 2025Article
- Revisiting theNPJ drug discovery · 2025Article
- CryptoBench: cryptic protein-ligand binding sites dataset and benchmark.Bioinformatics (Oxford, England) · 2024Article
- Predicting multiple conformations of ligand binding sites in proteins suggests that AlphaFold2 may remember too much.Proceedings of the National Academy of Sciences of the United States of America · 2024Article
- Exploration of Cryptic Pockets Using Enhanced Sampling Along Normal Modes: A Case Study of KRASJournal of chemical information and modeling · 2024Article
- Which cryptic sites are feasible drug targets?Drug discovery today · 2024Review
- Integrative residue-intuitive machine learning and MD Approach to Unveil Allosteric Site and Mechanism for β2AR.Nature communications · 2024Article
- The Malaria Box molecules: a source for targeting the RBD and NTD cryptic pocket of the spike glycoprotein in SARS-CoV-2.Journal of molecular modeling · 2024Article
15 more citing papers are in PubMed but not listed here.
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Authors and funding
8 authors at 2 institutions in 1 country.
Funding
Abstract
Molecular dynamics (MD) simulations of proteins reveal the existence of many transient surface pockets; however, the factors determining what small subset of these represent druggable or functionally relevant ligand binding sites, called "cryptic sites," are not understood. Here, we examine multiple X-ray structures for a set of proteins with validated cryptic sites, using the computational hot spot identification tool FTMap. The results show that cryptic sites in ligand-free structures generally have a strong binding energy hot spot very close by. As expected, regions around cryptic sites exhibit above-average flexibility, and close to 50% of the proteins studied here have unbound structures that could accommodate the ligand without clashes. Nevertheless, the strong hot spot neighboring each cryptic site is almost always exploited by the bound ligand, suggesting that binding may frequently involve an induced fit component. We additionally evaluated the structural basis for cryptic site formation, by comparing unbound to bound structures. Cryptic sites are most frequently occluded in the unbound structure by intrusion of loops (22.5%), side chains (19.4%), or in some cases entire helices (5.4%), but motions that create sites that are too open can also eliminate pockets (19.4%). The flexibility of cryptic sites frequently leads to missing side chains or loops (12%) that are particularly evident in low resolution crystal structures. An interesting observation is that cryptic sites formed solely by the movement of side chains, or of backbone segments with fewer than five residues, result only in low affinity binding sites with limited use for drug discovery.
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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.