ArticleBiology2015
Enrichment of druggable conformations from apo protein structures using cosolvent-accelerated molecular dynamics.
Article in Biology, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 13 papers.
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Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
13 citing papers in PubMed.
- Modeling Ligand Binding Site Water Networks with Site Identification by Ligand Competitive Saturation: Impact on Ligand Binding Orientations and Relative Binding Affinities.Journal of chemical theory and computation · 2024Article
- Which cryptic sites are feasible drug targets?Drug discovery today · 2024Review
- Article
- Enhancing SILCS-MC via GPU Acceleration and Ligand Conformational Optimization with Genetic and Parallel Tempering Algorithms.The journal of physical chemistry. B · 2024Article
- Review
- Application of Site-Identification by Ligand Competitive Saturation in Computer-Aided Drug Design.New journal of chemistry = Nouveau journal de chimie · 2022Article
- An Insight of RuBisCO Evolution through a Multilevel Approach.Biomolecules · 2021Article
- Cosolvent and Dynamic Effects in Binding Pocket Search by Docking Simulations.Journal of chemical information and modeling · 2021Article
- Identification of Cryptic Binding Sites Using MixMD with Standard and Accelerated Molecular Dynamics.Journal of chemical information and modeling · 2021Article
- 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
- Localization of Millisecond Dynamics: Dihedral Entropy from Accelerated MD.Journal of chemical theory and computation · 2016Article
- Protein Ensembles: How Does Nature Harness Thermodynamic Fluctuations for Life? The Diverse Functional Roles of Conformational Ensembles in the Cell.Chemical reviews · 2016Review
Corrections and comments
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Authors and funding
3 authors.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Here we describe the development of an improved workflow for utilizing experimental and simulated protein conformations in the structure-based design of inhibitors for anti-apoptotic Bcl-2 family proteins. Traditional structure-based approaches on similar targets are often constrained by the sparsity of available structures and difficulties in finding lead compounds that dock against flat, flexible protein-protein interaction surfaces. By employing computational docking of known small molecule inhibitors, we have demonstrated that structural ensembles derived from either accelerated MD (aMD) or MD in the presence of an organic cosolvent generally give better scores than those assessed from analogous conventional MD. Furthermore, conformations obtained from combined cosolvent aMD simulations started with the apo-Bcl-xL structure yielded better average and minimum docking scores for known binders than an ensemble of 72 experimental apo- and ligand-bound Bcl-xL structures. A detailed analysis of the simulated conformations indicates that the aMD effectively enhanced conformational sampling of the flexible helices flanking the main Bcl-xL binding groove, permitting the cosolvent acting as small ligands to penetrate more deeply into the binding pocket and shape ligand-bound conformations not evident in conventional simulations. We believe this approach could be useful for identifying inhibitors against other protein-protein interaction systems involving highly flexible binding sites, particularly for targets with less accumulated structural data.
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Registered trials
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