Einzeltreffer — DigiBib

The C-X-C chemokine receptor type 4 (CXCR4) is a potential therapeutic target for HIV infection, metastatic cancer, and inflammatory autoimmune diseases. In this study, we screened the ZINC chemical database for novel CXCR4 modulators through a series of in silico guided processes. After evaluating the screened compounds for their binding affinities to CXCR4 and inhibitory activities against the chemoattractant CXCL12, we identified a hit compound (ZINC 72372983) showing 100 nM affinity and 69% chemotaxis inhibition at the same concentration (100 nM). To increase the potency of our hit compound, we explored the protein-ligand interactions at an atomic level using molecular dynamics simulation which enabled us to design and synthesize a novel compound (Z7R) with nanomolar affinity (IC 50 = 1.25 nM) and improved chemotaxis inhibition (78.5%). Z7R displays promising anti-inflammatory activity (50%) in a mouse edema model by blocking CXCR4-expressed leukocytes, being supported by our immunohistochemistry study.

Competing Interests: Declaration of competing interest All authors have no conflict of interest to declare.

Titel:	Discovery of novel aminopiperidinyl amide CXCR4 modulators through virtual screening and rational drug design.
Autor/in / Beteiligte Person:	Oum, YH ; Kell, SA ; Yoon, Y ; Liang, Z ; Burger, P ; Shim, H
Link:	Zum Volltext
Zeitschrift:	European journal of medicinal chemistry, Jg. 201 (2020-09-01), S. 112479
Veröffentlichung:	Paris : Editions Scientifiques Elsevier ; <i>Original Publication</i>: Paris, S.E.C.T. [etc.], 2020
Medientyp:	academicJournal
ISSN:	1768-3254 (electronic)
DOI:	10.1016/j.ejmech.2020.112479
Schlagwort:	Animals Anti-Inflammatory Agents chemical synthesis Anti-Inflammatory Agents metabolism Cell Line, Tumor Drug Design Humans Mice Molecular Docking Simulation Molecular Dynamics Simulation Molecular Structure Piperidines chemical synthesis Piperidines metabolism Protein Binding Structure-Activity Relationship Anti-Inflammatory Agents therapeutic use Inflammation drug therapy Piperidines therapeutic use Receptors, CXCR4 metabolism
Sonstiges:	Nachgewiesen in: MEDLINE Sprachen: English Publication Type: Journal Article Language: English [Eur J Med Chem] 2020 Sep 01; Vol. 201, pp. 112479. <i>Date of Electronic Publication: </i>2020 Jun 06. MeSH Terms: Anti-Inflammatory Agents / therapeutic use ; Inflammation / drug therapy ; Piperidines / therapeutic use ; Receptors, CXCR4 / metabolism ; Animals ; Anti-Inflammatory Agents / chemical synthesis ; Anti-Inflammatory Agents / metabolism ; Cell Line, Tumor ; Drug Design ; Humans ; Mice ; Molecular Docking Simulation ; Molecular Dynamics Simulation ; Molecular Structure ; Piperidines / chemical synthesis ; Piperidines / metabolism ; Protein Binding ; Structure-Activity Relationship References: Exp Mol Med. 2010 Jun 30;42(6):465-72. (PMID: 20498529) ; Oncotarget. 2016 Oct 4;7(40):65109-65124. (PMID: 27556298) ; Environ Health Perspect. 1999 Feb;107 Suppl 1:25-35. (PMID: 10229704) ; J Mol Graph Model. 2015 Jul;60:1-14. (PMID: 26080355) ; J Med Chem. 2012 Jul 26;55(14):6582-94. (PMID: 22716043) ; Mol Pharmacol. 2008 Dec;74(6):1485-95. (PMID: 18768385) ; J Chem Inf Model. 2005 Jan-Feb;45(1):177-82. (PMID: 15667143) ; Future Med Chem. 2016;8(2):93-106. (PMID: 26807787) ; Nat Rev Drug Discov. 2013 Jan;12(1):25-34. (PMID: 23237917) ; Eur J Med Chem. 2017 Oct 20;139:519-530. (PMID: 28826086) ; Chembiochem. 2014 Jul 21;15(11):1614-20. (PMID: 24990206) ; Proc Natl Acad Sci U S A. 2012 Apr 3;109(14):5517-22. (PMID: 22431600) ; J Med Chem. 1999 Sep 23;42(19):3971-81. (PMID: 10508445) ; Antimicrob Agents Chemother. 2015 Apr;59(4):1895-904. (PMID: 25583709) ; Nat Rev Immunol. 2011 May;11(5):355-63. (PMID: 21494268) ; J Med Chem. 2010 Feb 11;53(3):1250-60. (PMID: 20043638) ; Methods Enzymol. 2009;461:249-79. (PMID: 19480923) ; J Med Chem. 2012 Feb 9;55(3):977-94. (PMID: 22085380) ; Science. 2015 Mar 6;347(6226):1117-22. (PMID: 25612609) ; J Med Chem. 2010 Apr 8;53(7):2719-40. (PMID: 20131845) ; Nat Rev Drug Discov. 2003 Jul;2(7):581-7. (PMID: 12815382) ; PLoS One. 2013 Sep 13;8(9):e74548. (PMID: 24058588) ; Nat Genet. 2003 May;34(1):70-4. (PMID: 12692554) ; Sci Rep. 2016 Jul 26;6:30155. (PMID: 27456816) ; J Med Chem. 2007 Jan 11;50(1):74-82. (PMID: 17201411) ; J Med Chem. 2008 Dec 25;51(24):7915-20. (PMID: 19053768) ; Drug Discov Today Technol. 2004 Dec;1(4):337-41. (PMID: 24981612) ; Science. 2010 Nov 19;330(6007):1066-71. (PMID: 20929726) ; J Med Chem. 2007 Nov 15;50(23):5655-64. (PMID: 17958344) ; Bioorg Med Chem Lett. 2008 Jul 15;18(14):4124-9. (PMID: 18539453) ; J Med Chem. 2004 Mar 25;47(7):1739-49. (PMID: 15027865) ; Curr Pharm Des. 2008;14(4):385-404. (PMID: 18289065) ; Arthritis Res Ther. 2010;12(5):R188. (PMID: 20939892) ; J Enzyme Inhib Med Chem. 2002 Apr;17(2):69-76. (PMID: 12420752) ; Proteins. 2011 Oct;79(10):2794-812. (PMID: 21905107) ; Eur J Pharmacol. 2015 Jan 5;746:363-7. (PMID: 25016087) ; Biochem Res Int. 2012;2012:951539. (PMID: 22482055) ; FEBS Lett. 2003 Jul 10;546(2-3):300-6. (PMID: 12832058) ; J Med Chem. 2010 Dec 23;53(24):8556-68. (PMID: 21105715) ; J Immunol. 2009 Apr 1;182(7):4448-58. (PMID: 19299746) ; Mol Pharmacol. 2018 Feb;93(2):141-156. (PMID: 29242355) ; Expert Opin Investig Drugs. 2010 Mar;19(3):345-55. (PMID: 20113217) ; J Biol Chem. 2007 Sep 14;282(37):27354-65. (PMID: 17599916) ; Theranostics. 2013;3(1):47-75. (PMID: 23382786) ; ChemMedChem. 2013 Apr;8(4):622-32. (PMID: 23468189) ; J Leukoc Biol. 2009 Nov;86(5):1111-8. (PMID: 19581373) ; J Mol Graph Model. 2014 Apr;49:25-37. (PMID: 24473069) ; Theranostics. 2013;3(1):40-6. (PMID: 23382785) ; Antimicrob Agents Chemother. 2000 Jun;44(6):1667-73. (PMID: 10817726) ; J Med Chem. 2009 Jun 11;52(11):3591-5. (PMID: 19425597) ; PLoS One. 2012;7(4):e34038. (PMID: 22485156) ; J Immunol. 2001 Oct 15;167(8):4686-92. (PMID: 11591799) ; Viruses. 2012 Feb;4(2):309-24. (PMID: 22470838) ; Br J Pharmacol. 2012 Mar;165(6):1617-1643. (PMID: 21699506) ; Molecules. 2019 Feb 02;24(3):. (PMID: 30717348) ; J Chem Inf Model. 2013 May 24;53(5):1043-56. (PMID: 23577723) ; Nat Rev Drug Discov. 2004 Nov;3(11):935-49. (PMID: 15520816) ; Drug Discov Today. 2011 Aug;16(15-16):659-70. (PMID: 21723955) ; J Biol Chem. 2001 Apr 27;276(17):14153-60. (PMID: 11154697) Grant Information: U01 EB028145 United States EB NIBIB NIH HHS Contributed Indexing: Keywords: C-X-C chemokine receptor type 4 (CXCR4); Chemokine modulator; Ligand shape similarity; Molecular docking; Molecular dynamics; Structure-based drug design Substance Nomenclature: 0 (Anti-Inflammatory Agents) ; 0 (CXCR4 protein, human) ; 0 (Piperidines) ; 0 (Receptors, CXCR4) Entry Date(s): Date Created: 20200614 Date Completed: 20210406 Latest Revision: 20210903 Update Code: 20240513 PubMed Central ID: PMC7422936

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Discovery of novel aminopiperidinyl amide CXCR4 modulators through virtual screening and rational drug design.