ArticlePLoS computational biology2022
How does a small molecule bind at a cryptic binding site?
Article in PLoS computational biology, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 25 papers.
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Who cites it
25 citing papers in PubMed, 48 citations in OpenAlex.
- Uncovering hidden druggable sites: computational approaches to allosteric and cryptic pocket discovery-from molecular dynamics to AI.Journal of computer-aided molecular design · 2026Review
- Biophysical insights into a cryptic ligand site in the hydrophobic core of human PCNA.Biophysical journal · 2026Article
- Directional information flow as a tool for analyzing protein allostery.bioRxiv : the preprint server for biology · 2026Article
- Residue-Level Affinity Decomposition via Quantum Electron Density: A Multivariable Framework Applied to HIV-1 Protease Inhibitors.The journal of physical chemistry. B · 2026Article
- A Comparative Review of Artificial Intelligence Applications in Small Molecule Versus Peptide Drug Discovery.International journal of molecular sciences · 2026Review
- MSCMF-DTB: a multi-scale cross-modal fusion framework for drug-target binding prediction.Scientific reports · 2026Article
- Decrypting cryptic pockets with physics-based simulations and artificial intelligence.Current opinion in structural biology · 2026Review
- Boosting Drug Discovery: Expanding the Applicability of Fragment Dissolved Molecular Dynamics to Accelerate Binding Mode Elucidation.Journal of chemical information and modeling · 2025Article
- Identification of Protein Cryptic Sites via Conformational Dynamics Capturing and Water-Based Pocket Characterization in Molecular Dynamics Simulations.Journal of chemical theory and computation · 2025Article
- Protein aggregation and neurodegenerative disease: Structural outlook for the novel therapeutics.Proteins · 2025Review
- Integrating Hydrogen Exchange with Molecular Dynamics for Improved Ligand Binding Predictions.Journal of chemical information and modeling · 2025Article
- Bayesian Inference of Binding Kinetics from Fluorescence Time Series.The journal of physical chemistry. B · 2025Article
- Design of immunogens to present a tumor-specific cryptic epitope.Scientific reports · 2025Article
- mTOR Variants Activation Discovers PI3K-like Cryptic Pocket, Expanding Allosteric, Mutant-Selective Inhibitor Designs.Journal of chemical information and modeling · 2025Article
- Exploration of Cryptic Pockets Using Enhanced Sampling Along Normal Modes: A Case Study of KRASJournal of chemical information and modeling · 2024Article
- Unbiased MD simulations identify lipid binding sites in lipid transfer proteins.The Journal of cell biology · 2024Article
- Article
- Which cryptic sites are feasible drug targets?Drug discovery today · 2024Review
- CytoSIP: an annotated structural atlas for interactions involving cytokines or cytokine receptors.Communications biology · 2024Article
- Interfacial Interactions between Nanoplastics and Biological Systems: toward an Atomic and Molecular Understanding of Plastics-Driven Biological Dyshomeostasis.ACS applied materials & interfaces · 2024Article
Corrections and comments
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Authors and funding
6 authors at 1 institution in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Protein-protein interactions (PPIs) are ubiquitous biomolecular processes that are central to virtually all aspects of cellular function. Identifying small molecules that modulate specific disease-related PPIs is a strategy with enormous promise for drug discovery. The design of drugs to disrupt PPIs is challenging, however, because many potential drug-binding sites at PPI interfaces are "cryptic": When unoccupied by a ligand, cryptic sites are often flat and featureless, and thus not readily recognizable in crystal structures, with the geometric and chemical characteristics of typical small-molecule binding sites only emerging upon ligand binding. The rational design of small molecules to inhibit specific PPIs would benefit from a better understanding of how such molecules bind at PPI interfaces. To this end, we have conducted unbiased, all-atom MD simulations of the binding of four small-molecule inhibitors (SP4206 and three SP4206 analogs) to interleukin 2 (IL2)-which performs its function by forming a PPI with its receptor-without incorporating any prior structural information about the ligands' binding. In multiple binding events, a small molecule settled into a stable binding pose at the PPI interface of IL2, resulting in a protein-small-molecule binding site and pose virtually identical to that observed in an existing crystal structure of the IL2-SP4206 complex. Binding of the small molecule stabilized the IL2 binding groove, which when the small molecule was not bound emerged only transiently and incompletely. Moreover, free energy perturbation (FEP) calculations successfully distinguished between the native and non-native IL2-small-molecule binding poses found in the simulations, suggesting that binding simulations in combination with FEP may provide an effective tool for identifying cryptic binding sites and determining the binding poses of small molecules designed to disrupt PPI interfaces by binding to such sites.
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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.