دورية أكاديمية
Identifying and Assessing Putative Allosteric Sites and Modulators for CXCR4 Predicted through Network Modeling and Site Identification by Ligand Competitive Saturation.
| العنوان: | Identifying and Assessing Putative Allosteric Sites and Modulators for CXCR4 Predicted through Network Modeling and Site Identification by Ligand Competitive Saturation. |
|---|---|
| المؤلفون: | Inan T; Department of Chemical Engineering, Istanbul Technical University, Istanbul 34469, Turkey., Flinko R; Institute of Human Virology, University of Maryland School of Medicine, Baltimore, Maryland 21201, United States., Lewis GK; Institute of Human Virology, University of Maryland School of Medicine, Baltimore, Maryland 21201, United States., MacKerell AD Jr; University of Maryland Computer-Aided Drug Design Center, Department of Pharmaceutical Sciences, School of Pharmacy, University of Maryland, Baltimore, Maryland 21201, United States., Kurkcuoglu O; Department of Chemical Engineering, Istanbul Technical University, Istanbul 34469, Turkey. |
| المصدر: | The journal of physical chemistry. B [J Phys Chem B] 2024 May 30; Vol. 128 (21), pp. 5157-5174. Date of Electronic Publication: 2024 Apr 22. |
| نوع المنشور: | Journal Article |
| اللغة: | English |
| بيانات الدورية: | Publisher: American Chemical Society Country of Publication: United States NLM ID: 101157530 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1520-5207 (Electronic) Linking ISSN: 15205207 NLM ISO Abbreviation: J Phys Chem B Subsets: MEDLINE |
| أسماء مطبوعة: | Original Publication: Washington, D.C. : American Chemical Society, c1997- |
| مواضيع طبية MeSH: | Receptors, CXCR4*/chemistry , Receptors, CXCR4*/metabolism , Receptors, CXCR4*/antagonists & inhibitors , Allosteric Site*, Ligands ; Humans ; Molecular Docking Simulation ; Monte Carlo Method ; Allosteric Regulation |
| مستخلص: | The chemokine receptor CXCR4 is a critical target for the treatment of several cancer types and HIV-1 infections. While orthosteric and allosteric modulators have been developed targeting its extracellular or transmembrane regions, the intramembrane region of CXCR4 may also include allosteric binding sites suitable for the development of allosteric drugs. To investigate this, we apply the Gaussian Network Model (GNM) to the monomeric and dimeric forms of CXCR4 to identify residues essential for its local and global motions located in the hinge regions of the protein. Residue interaction network (RIN) analysis suggests hub residues that participate in allosteric communication throughout the receptor. Mutual residues from the network models reside in regions with a high capacity to alter receptor dynamics upon ligand binding. We then investigate the druggability of these potential allosteric regions using the site identification by ligand competitive saturation (SILCS) approach, revealing two putative allosteric sites on the monomer and three on the homodimer. Two screening campaigns with Glide and SILCS-Monte Carlo docking using FDA-approved drugs suggest 20 putative hit compounds including antifungal drugs, anticancer agents, HIV protease inhibitors, and antimalarial drugs. In vitro assays considering mAB 12G5 and CXCL12 demonstrate both positive and negative allosteric activities of these compounds, supporting our computational approach. However, in vivo functional assays based on the recruitment of β-arrestin to CXCR4 do not show significant agonism and antagonism at a single compound concentration. The present computational pipeline brings a new perspective to computer-aided drug design by combining conformational dynamics based on network analysis and cosolvent analysis based on the SILCS technology to identify putative allosteric binding sites using CXCR4 as a showcase. |
| References: | Biophys J. 2013 Sep 17;105(6):1502-14. (PMID: 24048002) Adv Cancer Res. 2014;124:31-82. (PMID: 25287686) Bioorg Med Chem Lett. 2022 May 15;64:128654. (PMID: 35259487) J Chem Inf Model. 2011 Apr 25;51(4):877-96. (PMID: 21456594) PLoS Comput Biol. 2018 Mar 12;14(3):e1006062. (PMID: 29529028) Science. 1996 Jan 19;271(5247):363-6. (PMID: 8553074) Mol Pharmacol. 2019 Dec;96(6):737-752. (PMID: 31548340) Antivir Chem Chemother. 2019 Jan-Dec;27:2040206619829382. (PMID: 30776910) Bioorg Med Chem Lett. 2024 Jan 1;97:129548. (PMID: 37949379) J Chem Inf Model. 2020 Dec 28;60(12):6447-6461. (PMID: 33231066) Chem Sci. 2021 May 25;12(25):8844-8858. (PMID: 34257885) Proteins. 2021 Nov;89(11):1425-1441. (PMID: 34169568) Front Immunol. 2020 Aug 28;11:2109. (PMID: 32983169) J Chem Inf Model. 2021 Apr 26;61(4):1931-1941. (PMID: 33819021) Proc Natl Acad Sci U S A. 2020 Nov 17;117(46):29144-29154. (PMID: 33148803) Curr Opin Struct Biol. 2017 Aug;45:150-159. (PMID: 28558341) Methods Cell Biol. 2016;132:233-54. (PMID: 26928547) J Comput Aided Mol Des. 2013 Mar;27(3):221-34. (PMID: 23579614) J Chem Inf Model. 2009 Oct;49(10):2356-68. (PMID: 19761201) J Chem Inf Model. 2013 Nov 25;53(11):2926-36. (PMID: 24127817) Biomol Ther (Seoul). 2018 Sep 1;26(5):494-502. (PMID: 30092625) J Chem Inf Model. 2020 Dec 28;60(12):6489-6501. (PMID: 33196188) J Comput Chem. 2010 Mar;31(4):671-90. (PMID: 19575467) Anal Biochem. 2003 Mar 1;314(1):16-29. (PMID: 12633598) Proc Natl Acad Sci U S A. 2016 Aug 30;113(35):9928-33. (PMID: 27543332) J Chem Inf Model. 2015 Mar 23;55(3):700-8. (PMID: 25692383) J Biol Chem. 2021 Jan-Jun;296:100139. (PMID: 33268380) Oncotarget. 2015 Mar 10;6(7):5022-40. (PMID: 25669980) Int J Mol Sci. 2014 May 06;15(5):7841-64. (PMID: 24806342) Nature. 2019 May;569(7755):289-292. (PMID: 31019305) J Med Chem. 2006 Oct 19;49(21):6177-96. (PMID: 17034125) Fold Des. 1997;2(3):173-81. (PMID: 9218955) Science. 2010 Nov 19;330(6007):1066-71. (PMID: 20929726) Nature. 1996 Oct 3;383(6599):447-50. (PMID: 8837779) J Biol Chem. 2001 Nov 16;276(46):42826-33. (PMID: 11551942) J Mol Graph Model. 2015 Jul;60:1-14. (PMID: 26080355) PLoS Comput Biol. 2018 Jun 18;14(6):e1006209. (PMID: 29912865) Eur J Med Chem. 2018 Jun 25;154:68-90. (PMID: 29777988) J Chem Theory Comput. 2021 Jul 13;17(7):4291-4300. (PMID: 34096718) J Am Chem Soc. 2011 Oct 12;133(40):15878-81. (PMID: 21905700) J Comput Aided Mol Des. 2019 Jun;33(6):573-595. (PMID: 31123958) Cell. 1999 Mar 5;96(5):667-76. (PMID: 10089882) Angew Chem Int Ed Engl. 2018 Mar 12;57(12):3048-3053. (PMID: 29405531) J Recept Signal Transduct Res. 2000 Nov;20(4):189-210. (PMID: 11192018) PLoS Comput Biol. 2009 Jul;5(7):e1000435. (PMID: 19593374) Drug Discov Today. 2024 Mar;29(3):103848. (PMID: 38052317) Front Immunol. 2021 May 28;12:668758. (PMID: 34122427) J Med Chem. 2004 Mar 25;47(7):1739-49. (PMID: 15027865) Science. 2013 Sep 20;341(6152):1387-90. (PMID: 24030490) Nature. 2015 Apr 16;520(7547):317-21. (PMID: 25822790) Antimicrob Agents Chemother. 2007 Jul;51(7):2351-8. (PMID: 17452489) Cell Death Dis. 2021 May 8;12(5):464. (PMID: 33966046) PLoS One. 2017 Nov 10;12(11):e0187949. (PMID: 29125867) Nature. 2011 Jul 19;477(7366):549-55. (PMID: 21772288) Biochim Biophys Acta Gen Subj. 2020 Apr;1864(4):129519. (PMID: 31911242) Bioorg Med Chem. 2021 May 15;38:116136. (PMID: 33894490) Mol Pharmacol. 2019 Nov;96(5):527-541. (PMID: 30967440) PLoS One. 2013 Sep 02;8(9):e74320. (PMID: 24023934) Turk J Biol. 2018 Oct 25;42(5):392-404. (PMID: 30930623) Cell. 1996 Nov 15;87(4):745-56. (PMID: 8929542) Front Mol Biosci. 2020 Sep 25;7:586075. (PMID: 33102529) J Mol Biol. 2006 Jun 23;359(5):1400-9. (PMID: 16725153) Nature. 2014 Sep 4;513(7516):124-7. (PMID: 25043059) J Chem Theory Comput. 2014 Jun 10;10(6):2281-2290. (PMID: 24932136) J Comput Chem. 2008 Aug;29(11):1859-65. (PMID: 18351591) Sci Rep. 2017 Dec 4;7(1):16873. (PMID: 29203889) Nat Struct Mol Biol. 2017 Jul;24(7):570-577. (PMID: 28581512) Nature. 1996 Aug 29;382(6594):833-5. (PMID: 8752281) Biophys J. 2003 Jan;84(1):171-84. (PMID: 12524273) Biochim Biophys Acta Mol Basis Dis. 2018 Nov;1864(11):3837-3846. (PMID: 30251699) Mol Pharmacol. 1999 Jan;55(1):67-73. (PMID: 9882699) Nat Rev Drug Discov. 2021 Sep;20(9):710-722. (PMID: 34257432) J Med Chem. 2014 Jul 24;57(14):5845-59. (PMID: 24471928) Proc Natl Acad Sci U S A. 2010 Dec 21;107(51):22255-9. (PMID: 21139054) J Chem Inf Model. 2013 Dec 23;53(12):3384-98. (PMID: 24245913) Nature. 2017 May 4;545(7652):112-115. (PMID: 28445455) J Chem Inf Model. 2019 Jun 24;59(6):3018-3035. (PMID: 31034213) Science. 1996 Nov 1;274(5288):768-70. (PMID: 8864113) Nature. 1996 Aug 15;382(6592):635-8. (PMID: 8757135) J Comput Aided Mol Des. 2009 Aug;23(8):541-54. (PMID: 19421721) Nature. 2019 May;569(7755):284-288. (PMID: 31019306) J Mol Biol. 2022 Sep 15;434(17):167569. (PMID: 35378118) J Biol Chem. 2002 Aug 16;277(33):29484-9. (PMID: 12034737) Cochrane Database Syst Rev. 2015 Oct 20;(10):CD010615. (PMID: 26484982) Cell Chem Biol. 2019 May 16;26(5):662-673.e7. (PMID: 30827936) Int J Mol Sci. 2016 Jun 20;17(5):. (PMID: 27331810) Biochim Biophys Acta Gen Subj. 2017 Dec;1861(12):3131-3141. (PMID: 28917952) Arch Pharm (Weinheim). 2022 Jan;355(1):e2100158. (PMID: 34559414) Phys Chem Chem Phys. 2018 Oct 3;20(38):24915-24920. (PMID: 30238101) Curr Med Chem. 2010;17(8):741-9. (PMID: 20088758) J Biol Chem. 2003 Jan 10;278(2):896-907. (PMID: 12417595) Phys Rev Lett. 2009 Feb 27;102(8):088103. (PMID: 19257794) Mol Pharmacol. 2019 Dec;96(6):753-764. (PMID: 31481460) Sci Rep. 2019 Feb 20;9(1):2399. (PMID: 30787324) PLoS Comput Biol. 2016 Nov 3;12(11):e1005169. (PMID: 27812115) Proc Natl Acad Sci U S A. 2002 Jan 22;99(2):643-8. (PMID: 11805322) Future Med Chem. 2020 Jul;12(13):1213-1225. (PMID: 32515227) J Mol Biol. 2002 Jul 12;320(3):597-608. (PMID: 12096912) J Virol. 2001 Oct;75(19):8957-67. (PMID: 11533159) Mol Cancer Ther. 2006 Oct;5(10):2474-83. (PMID: 17041091) J Virol. 1997 Jun;71(6):4744-51. (PMID: 9151868) Methods Mol Biol. 2019;1947:257-267. (PMID: 30969421) J Phys Chem B. 2010 Jun 17;114(23):7830-43. (PMID: 20496934) J Chem Inf Model. 2015 Nov 23;55(11):2324-37. (PMID: 26479676) Commun Chem. 2020 Oct 8;3(1):133. (PMID: 36703316) Phys Rev Lett. 2008 Jun 6;100(22):228102. (PMID: 18643462) Cancer Lett. 2017 Jan 28;385:128-136. (PMID: 27810405) Front Pharmacol. 2019 Nov 07;10:1310. (PMID: 31787895) Bioorg Med Chem Lett. 2012 Mar 15;22(6):2146-50. (PMID: 22365757) Stem Cell Res Ther. 2021 Jan 7;12(1):17. (PMID: 33413613) Nucleic Acids Res. 2010 Jul;38(Web Server issue):W417-23. (PMID: 20478828) Nature. 1996 Aug 29;382(6594):829-33. (PMID: 8752280) Biophys Chem. 2022 Jan;280:106701. (PMID: 34736071) Nat Rev Immunol. 2011 Aug 25;11(9):597-606. (PMID: 21866172) Biophys J. 2015 Sep 15;109(6):1190-201. (PMID: 26338442) Sci Rep. 2020 Sep 28;10(1):15901. (PMID: 32985550) J Biol Chem. 2012 Apr 13;287(16):12787-96. (PMID: 22374997) J Biol Chem. 2007 Aug 31;282(35):25677-86. (PMID: 17591774) Nat Methods. 2017 Jan;14(1):71-73. (PMID: 27819658) Annu Rev Biochem. 2018 Jun 20;87:897-919. (PMID: 29925258) J Med Chem. 2004 Mar 25;47(7):1750-9. (PMID: 15027866) Nature. 2016 Apr 25;533(7602):274-7. (PMID: 27111510) Proteins. 2004 May 1;55(2):351-67. (PMID: 15048827) J Virol. 2005 Oct;79(20):12667-73. (PMID: 16188969) J Virol. 2005 Feb;79(3):1930-3. (PMID: 15650218) |
| معلومات مُعتمدة: | R35 GM131710 United States GM NIGMS NIH HHS |
| المشرفين على المادة: | 0 (Receptors, CXCR4) 0 (Ligands) 0 (CXCR4 protein, human) |
| تواريخ الأحداث: | Date Created: 20240422 Date Completed: 20240530 Latest Revision: 20240607 |
| رمز التحديث: | 20240607 |
| مُعرف محوري في PubMed: | PMC11139592 |
| DOI: | 10.1021/acs.jpcb.4c00925 |
| PMID: | 38647430 |
| قاعدة البيانات: | MEDLINE |
Find this issue from the American Chemical Society | تدمد: | 1520-5207 |
|---|---|
| DOI: | 10.1021/acs.jpcb.4c00925 |