دورية أكاديمية
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Chemical validation of a druggable site on Hsp27/HSPB1 using in silico solvent mapping and biophysical methods.

التفاصيل البيبلوغرافية
العنوان: Chemical validation of a druggable site on Hsp27/HSPB1 using in silico solvent mapping and biophysical methods.
المؤلفون: Makley LN; Department of Pharmaceutical Chemistry and the Institute for Neurodegenerative Disease, University of California at San Francisco, San Francisco, CA 94158, United States; Department of Medicinal Chemistry, University of Michigan, Ann Arbor, MI 48109, United States., Johnson OT; Department of Pharmaceutical Chemistry and the Institute for Neurodegenerative Disease, University of California at San Francisco, San Francisco, CA 94158, United States., Ghanakota P; Department of Medicinal Chemistry, University of Michigan, Ann Arbor, MI 48109, United States., Rauch JN; Department of Pharmaceutical Chemistry and the Institute for Neurodegenerative Disease, University of California at San Francisco, San Francisco, CA 94158, United States., Osborn D; Department of Pharmaceutical Chemistry and the Institute for Neurodegenerative Disease, University of California at San Francisco, San Francisco, CA 94158, United States., Wu TS; Department of Pharmaceutical Chemistry and the Institute for Neurodegenerative Disease, University of California at San Francisco, San Francisco, CA 94158, United States., Cierpicki T; Department of Pathology, University of Michigan, Ann Arbor, MI, 48109, United States., Carlson HA; Department of Medicinal Chemistry, University of Michigan, Ann Arbor, MI 48109, United States., Gestwicki JE; Department of Pharmaceutical Chemistry and the Institute for Neurodegenerative Disease, University of California at San Francisco, San Francisco, CA 94158, United States. Electronic address: Jason.gestwicki@ucsf.edu.
المصدر: Bioorganic & medicinal chemistry [Bioorg Med Chem] 2021 Mar 15; Vol. 34, pp. 115990. Date of Electronic Publication: 2021 Jan 24.
نوع المنشور: Journal Article; Research Support, N.I.H., Extramural
اللغة: English
بيانات الدورية: Publisher: Elsevier Science Country of Publication: England NLM ID: 9413298 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1464-3391 (Electronic) Linking ISSN: 09680896 NLM ISO Abbreviation: Bioorg Med Chem Subsets: MEDLINE
أسماء مطبوعة: Publication: Oxford : Elsevier Science
Original Publication: Oxford : New York : Pergamon Press, c1993-
مواضيع طبية MeSH: Models, Chemical* , Molecular Dynamics Simulation*, Heat-Shock Proteins/*chemistry , Molecular Chaperones/*chemistry, Binding Sites ; Models, Molecular ; Mutation ; Protein Conformation ; Protein Domains ; Reproducibility of Results
مستخلص: Destabilizing mutations in small heat shock proteins (sHsps) are linked to multiple diseases; however, sHsps are conformationally dynamic, lack enzymatic function and have no endogenous chemical ligands. These factors render sHsps as classically "undruggable" targets and make it particularly challenging to identify molecules that might bind and stabilize them. To explore potential solutions, we designed a multi-pronged screening workflow involving a combination of computational and biophysical ligand-discovery platforms. Using the core domain of the sHsp family member Hsp27/HSPB1 (Hsp27c) as a target, we applied mixed solvent molecular dynamics (MixMD) to predict three possible binding sites, which we confirmed using NMR-based solvent mapping. Using this knowledge, we then used NMR spectroscopy to carry out a fragment-based drug discovery (FBDD) screen, ultimately identifying two fragments that bind to one of these sites. A medicinal chemistry effort improved the affinity of one fragment by ~50-fold (16 µM), while maintaining good ligand efficiency (~0.32 kcal/mol/non-hydrogen atom). Finally, we found that binding to this site partially restored the stability of disease-associated Hsp27 variants, in a redox-dependent manner. Together, these experiments suggest a new and unexpected binding site on Hsp27, which might be exploited to build chemical probes.
(Copyright © 2021 Elsevier Ltd. All rights reserved.)
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معلومات مُعتمدة: T32 GM007767 United States GM NIGMS NIH HHS; T32 GM140223 United States GM NIGMS NIH HHS; R01 GM065372 United States GM NIGMS NIH HHS; R01 NS059690 United States NS NINDS NIH HHS; K12 GM081266 United States GM NIGMS NIH HHS
فهرسة مساهمة: Keywords: Chaperone; DSF; Neuropathy; Small heat shock protein; Solvent mapping; Thermal stability; Undruggable
المشرفين على المادة: 0 (HSPB1 protein, human)
0 (Heat-Shock Proteins)
0 (Molecular Chaperones)
تواريخ الأحداث: Date Created: 20210207 Date Completed: 20210920 Latest Revision: 20231031
رمز التحديث: 20240628
مُعرف محوري في PubMed: PMC7968374
DOI: 10.1016/j.bmc.2020.115990
PMID: 33549906
قاعدة البيانات: MEDLINE
الوصف
تدمد:1464-3391
DOI:10.1016/j.bmc.2020.115990