ArticleJournal of computational chemistry2012
Balancing target flexibility and target denaturation in computational fragment-based inhibitor discovery.
Article in Journal of computational chemistry, 2012. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 21 papers.
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The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
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Who cites it
21 citing papers in PubMed, 42 citations in OpenAlex.
- SWISH-X, an Expanded Approach to Detect Cryptic Pockets in Proteins and at Protein-Protein Interfaces.Journal of chemical theory and computation · 2024Article
- How does a small molecule bind at a cryptic binding site?PLoS computational biology · 2022Article
- Assessing hERG1 Blockade from Bayesian Machine-Learning-Optimized Site Identification by Ligand Competitive Saturation Simulations.Journal of chemical information and modeling · 2020Article
- Simulations of mutant p53 DNA binding domains reveal a novel druggable pocket.Nucleic acids research · 2019Article
- Solvents to Fragments to Drugs: MD Applications in Drug Design.Molecules (Basel, Switzerland) · 2018Review
- Novel Noncatalytic Substrate-Selective p38α-Specific MAPK Inhibitors with Endothelial-Stabilizing and Anti-Inflammatory Activity.Journal of immunology (Baltimore, Md. : 1950) · 2017Article
- Computer-Aided Drug Design Methods.Methods in molecular biology (Clifton, N.J.) · 2017Article
- Driving Structure-Based Drug Discovery through Cosolvent Molecular Dynamics.Journal of medicinal chemistry · 2016Review
- Computational functional group mapping for drug discovery.Drug discovery today · 2016Review
- Benzene Probes in Molecular Dynamics Simulations Reveal Novel Binding Sites for Ligand Design.The journal of physical chemistry letters · 2016Article
- Identifying binding hot spots on protein surfaces by mixed-solvent molecular dynamics: HIV-1 protease as a test case.Biopolymers · 2016Article
- Overcoming Chemical, Biological, and Computational Challenges in the Development of Inhibitors Targeting Protein-Protein Interactions.Chemistry & biology · 2015Review
- Pharmacophore modeling using site-identification by ligand competitive saturation (SILCS) with multiple probe molecules.Journal of chemical information and modeling · 2015Article
- Site Identification by Ligand Competitive Saturation (SILCS) simulations for fragment-based drug design.Methods in molecular biology (Clifton, N.J.) · 2015Article
- Sampling of Organic Solutes in Aqueous and Heterogeneous Environments Using Oscillating Excess Chemical Potentials in Grand Canonical-like Monte Carlo-Molecular Dynamics Simulations.Journal of chemical theory and computation · 2014Article
- Site-Identification by Ligand Competitive Saturation (SILCS) assisted pharmacophore modeling.Journal of computer-aided molecular design · 2014Article
- Inclusion of multiple fragment types in the site identification by ligand competitive saturation (SILCS) approach.Journal of chemical information and modeling · 2013Article
- Improving protocols for protein mapping through proper comparison to crystallography data.Journal of chemical information and modeling · 2013Article
- The evolution of S100B inhibitors for the treatment of malignant melanoma.Future medicinal chemistry · 2013Review
- Druggable protein interaction sites are more predisposed to surface pocket formation than the rest of the protein surface.PLoS computational biology · 2013Article
Corrections and comments
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Authors and funding
3 authors at 2 institutions in 1 country.
Funding
Abstract
Accounting for target flexibility and selecting "hot spots" most likely to be able to bind an inhibitor continue to be challenges in the field of structure-based drug design, especially in the case of protein-protein interactions. Computational fragment-based approaches using molecular dynamics (MD) simulations are a promising emerging technology having the potential to address both of these challenges. However, the optimal MD conditions permitting sufficient target flexibility while also avoiding fragment-induced target denaturation remain ambiguous. Using one such technology (Site Identification by Ligand Competitive Saturation, SILCS), conditions were identified to either prevent denaturation or identify and exclude trajectories in which subtle but important denaturation was occurring. The target system used was the well-characterized protein cytokine IL-2, which is involved in a protein-protein interface and, in its unliganded crystallographic form, lacks surface pockets that can serve as small-molecule binding sites. Nonetheless, small-molecule inhibitors have previously been discovered that bind to two "cryptic" binding sites that emerge only in the presence of ligand binding, highlighting the important role of IL-2 flexibility. Using the above conditions, SILCS with hydrophobic fragments was able to identify both sites based on favorable fragment binding while avoiding IL-2 denaturation. An important additional finding was that acetonitrile, a water-miscible fragment, fails to identify either site yet can induce target denaturation, highlighting the importance of fragment choice.
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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.