دورية أكاديمية
Structure-based virtual screening identifies a small-molecule inhibitor of the profilin 1-actin interaction.
| العنوان: | Structure-based virtual screening identifies a small-molecule inhibitor of the profilin 1-actin interaction. |
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| المؤلفون: | Gau D; From the Departments of Bioengineering., Lewis T; Chemistry., McDermott L; Computational and Systems Biology., Wipf P; From the Departments of Bioengineering.; Chemistry., Koes D; Computational and Systems Biology., Roy P; From the Departments of Bioengineering, Partha.Roy@pitt.edu par19@pitt.edu.; Cell Biology, and.; Pathology, University of Pittsburgh, Pittsburgh, Pennsylvania 15219. |
| المصدر: | The Journal of biological chemistry [J Biol Chem] 2018 Feb 16; Vol. 293 (7), pp. 2606-2616. Date of Electronic Publication: 2017 Dec 27. |
| نوع المنشور: | Journal Article; Research Support, N.I.H., Extramural; Research Support, U.S. Gov't, Non-P.H.S. |
| اللغة: | English |
| بيانات الدورية: | Publisher: Elsevier Inc. on behalf of American Society for Biochemistry and Molecular Biology Country of Publication: United States NLM ID: 2985121R Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1083-351X (Electronic) Linking ISSN: 00219258 NLM ISO Abbreviation: J Biol Chem Subsets: MEDLINE |
| أسماء مطبوعة: | Publication: 2021- : [New York, NY] : Elsevier Inc. on behalf of American Society for Biochemistry and Molecular Biology Original Publication: Baltimore, MD : American Society for Biochemistry and Molecular Biology |
| مواضيع طبية MeSH: | Actins/*metabolism , Profilins/*metabolism , Small Molecule Libraries/*chemistry, Actin Cytoskeleton/genetics ; Actin Cytoskeleton/metabolism ; Actins/antagonists & inhibitors ; Actins/genetics ; Animals ; Aorta, Thoracic/metabolism ; Cell Movement/drug effects ; Cell Proliferation/drug effects ; Crystallography, X-Ray ; Drug Evaluation, Preclinical ; Endothelial Cells/cytology ; Endothelial Cells/metabolism ; Humans ; Mice ; Mice, Inbred C57BL ; Polymerization/drug effects ; Profilins/antagonists & inhibitors ; Profilins/chemistry ; Profilins/genetics ; Protein Binding/drug effects ; Small Molecule Libraries/pharmacology |
| مستخلص: | Profilin 1 (Pfn1) is an important regulator of the actin cytoskeleton and plays a vital role in many actin-based cellular processes. Therefore, identification of a small-molecule intervention strategy targeted against the Pfn1-actin interaction could have broad utility in cytoskeletal research and further our understanding of the role of Pfn1 in actin-mediated biological processes. Based on an already resolved Pfn1-actin complex crystal structure, we performed structure-based virtual screening of small-molecule libraries to seek inhibitors of the Pfn1-actin interaction. We identified compounds that match the pharmacophore of the key actin residues of Pfn1-actin interaction and therefore have the potential to act as competitive inhibitors of this interaction. Subsequent biochemical assays identified two candidate compounds with nearly identical structures that can mitigate the effect of Pfn1 on actin polymerization in vitro As a further proof-of-concept test for cellular effects of these compounds, we performed proximity ligation assays in endothelial cells (ECs) to demonstrate compound-induced inhibition of Pfn1-actin interaction. Consistent with the important role of Pfn1 in regulating actin polymerization and various fundamental actin-based cellular activities (migration and proliferation), treatment of these compounds reduced the overall level of cellular filamentous (F) actin, slowed EC migration and proliferation, and inhibited the angiogenic ability of ECs both in vitro and ex vivo In summary, this study provides the first proof of principle of small-molecule-mediated interference with the Pfn1-actin interaction. Our findings may have potential general utility for perturbing actin-mediated cellular activities and biological processes. (© 2018 by The American Society for Biochemistry and Molecular Biology, Inc.) |
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| معلومات مُعتمدة: | R01 CA108607 United States CA NCI NIH HHS; R01 GM108340 United States GM NIGMS NIH HHS; T32 HL076124 United States HL NHLBI NIH HHS; UL1 TR001857 United States TR NCATS NIH HHS |
| فهرسة مساهمة: | Keywords: actin; angiogenesis; cell migration; endothelial cell; molecular dynamics; pharmacophore; profilin; virtual screening |
| سلسلة جزيئية: | PDB 2BTF |
| المشرفين على المادة: | 0 (Actins) 0 (Profilins) 0 (Small Molecule Libraries) |
| تواريخ الأحداث: | Date Created: 20171229 Date Completed: 20190205 Latest Revision: 20210205 |
| رمز التحديث: | 20231215 |
| مُعرف محوري في PubMed: | PMC5818201 |
| DOI: | 10.1074/jbc.M117.809137 |
| PMID: | 29282288 |
| قاعدة البيانات: | MEDLINE |
| تدمد: | 1083-351X |
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| DOI: | 10.1074/jbc.M117.809137 |