Discovery of novel allosteric modulators targeting an extra-helical binding site of glp-1r using structure-and ligand-based virtual screening

Qingtong Zhou; Wanjing Guo; Antao Dai; Xiaoqing Cai; Márton Vass; Chris de Graaf; Wenqing Shui; Suwen Zhao; Dehua Yang; Ming Wei Wang

doi:10.3390/biom11070929

Discovery of novel allosteric modulators targeting an extra-helical binding site of glp-1r using structure-and ligand-based virtual screening

Qingtong Zhou, Wanjing Guo, Antao Dai, Xiaoqing Cai, Márton Vass, Chris de Graaf, Wenqing Shui, Suwen Zhao^*, Dehua Yang, Ming Wei Wang

^*Corresponding author for this work

Medicinal chemistry

Research output: Contribution to Journal › Article › Academic › peer-review

Abstract

Allosteric modulators have emerged with many potential pharmacological advantages as they do not compete the binding of agonist or antagonist to the orthosteric sites but ultimately affect downstream signaling. To identify allosteric modulators targeting an extra-helical binding site of the glucagon-like peptide-1 receptor (GLP-1R) within the membrane environment, the following two computational approaches were applied: structure-based virtual screening with consideration of lipid contacts and ligand-based virtual screening with the maintenance of specific allosteric pocket residue interactions. Verified by radiolabeled ligand binding and cAMP accumulation experiments, two negative allosteric modulators and seven positive allosteric modulators were discovered using structure-based and ligand-based virtual screening methods, respectively. The computational approach presented here could possibly be used to discover allosteric modulators of other G protein-coupled receptors.

Original language	English
Article number	929
Journal	Biomolecules
Volume	11
Issue number	7
DOIs	https://doi.org/10.3390/biom11070929
Publication status	Published - Jul 2021

Bibliographical note

Funding Information:
sFcurinpdt.ing: This research was partially supported by National Key Research and Development Pro-Funding: This research was partially supported by National Key Research and Development Program of China grants 2018YFA0507000 (S.Z. and M.-W.W.) and 2016YFC0905900 (S.Z.); National Fugnradmin go:f TChhiisnrae sgeraarncths w20a1s8 pYaFrAti0a5ll0y70su00p p(So.rZte. da nbdy MNa.-tWion.Wal.)KaenydR 2e0s1e6aYrcFhC a0n9d05D90e0v e(lSo.pZm.);e Nnta Ptiroon-al Mega R&D Program for Drug Discovery grants 2018ZX09711002-002-005 (D.Y.) and 2018ZX09735-grMameg ao fR C&hDin Par gograrnamts 2fo0r1 8DYrFuAg 0D5i0s7c0o0v0e r(yS .gZr. aanntds 2M01.-8WZX.W09.)71a1n0d0 22-001062Y-0F0C50 (9D0.5Y9.0)0a n(Sd. Z2.0)1; 8NZaXti0o9n7a3l5 - 001 (M.-W.W); National Natural Science Foundation of China grants 21704064 (Q.Z.), 81573479 M0e0g1a (RM&.-DW P.Wro)g; rNamat ifoonr aDl rNuga tDuriascl oSvceireyn cgeraFnotus n2d01a8tiZoXn 0o9f71C1h0i0n2a-0g0r2a-0n0ts5 2(D17.Y04.)0a6n4d ( Q20.Z18.)Z, X80195773354-79 (D.Y.), 81773792 (D.Y.), 81872915 (M.-W.W.), 82073904 (M.-W.W.) and 31971178 (S.Z.); Shanghai Sci-00(1D .(YM.).,-8W17.W73)7; 9N2 a(Dtio.Yn.a),l 8N18a7tu29ra1l5 S(Mcie.-nWce.WF.o)u, 8n2d0a7t3io9n04 o (fMC.-hWin.Wa .g)raanndts 3 12917710147086 4(S (.QZ..)Z; .S)h, a8n1g57h3a4i 7S9c i-ence & Technology Development Fund grant 16ZR1407100 (A.D.); Novo Nordisk-CAS Research (De.nYc.e), &81 7T7e3c7h9n2o (lDog.Yy. )D, 8e1v8e7l2o9p1m5 e(nMt .-FWun.Wd .g),r 8a2n0t7 1369Z04R (1M40.7-W10.0W (.A) a.Dnd.) ;3 N19o7v1o17N8 o(Srd.Zis.)k; -SChAanSg Rheasi eSacric-h Fund grant NNCAS-2017-1-CC (D.Y.) and annual overhead support from ShanghaiTech University enFcuen &d gTreacnhtn NoNloCgyA SD-e2v01e7lo-1p-mCeCn (tD F.uYn.)d a ngdra antn 1u6aZl Rov14e0rh71ea0d0 s(Aup.Dp.o);r tN froovmo SNhoarndgihska-iTCeAcSh URensievaerrcshit y and Chinese Academy of Sciences. Fuanndd gCrhainnte NseN ACcAadSe-2m0y1 7o-f1 -SCciCe n(Dce.sY. .) and annual overhead support from ShanghaiTech University

Funding Information:
Funding: This research was partially supported by National Key Research and Development Program of China grants 2018YFA0507000 (S.Z. and M.-W.W.) and 2016YFC0905900 (S.Z.); National Mega R&D Program for Drug Discovery grants 2018ZX09711002-002-005 (D.Y.) and 2018ZX09735-001 (M.-W.W); National Natural Science Foundation of China grants 21704064 (Q.Z.), 81573479 (D.Y.), 81773792 (D.Y.), 81872915 (M.-W.W.), 82073904 (M.-W.W.) and 31971178 (S.Z.); Shanghai Science & Technology Development Fund grant 16ZR1407100 (A.D.); Novo Nordisk-CAS Research Fund grant NNCAS-2017-1-CC (D.Y.) and annual overhead support from ShanghaiTech University and Chinese Academy of Sciences.

Publisher Copyright:
© 2021 by the authors. Licensee MDPI, Basel, Switzerland.

Copyright:
Copyright 2021 Elsevier B.V., All rights reserved.

Funding

sFcurinpdt.ing: This research was partially supported by National Key Research and Development Pro-Funding: This research was partially supported by National Key Research and Development Program of China grants 2018YFA0507000 (S.Z. and M.-W.W.) and 2016YFC0905900 (S.Z.); National Fugnradmin go:f TChhiisnrae sgeraarncths w20a1s8 pYaFrAti0a5ll0y70su00p p(So.rZte. da nbdy MNa.-tWion.Wal.)KaenydR 2e0s1e6aYrcFhC a0n9d05D90e0v e(lSo.pZm.);e Nnta Ptiroon-al Mega R&D Program for Drug Discovery grants 2018ZX09711002-002-005 (D.Y.) and 2018ZX09735-grMameg ao fR C&hDin Par gograrnamts 2fo0r1 8DYrFuAg 0D5i0s7c0o0v0e r(yS .gZr. aanntds 2M01.-8WZX.W09.)71a1n0d0 22-001062Y-0F0C50 (9D0.5Y9.0)0a n(Sd. Z2.0)1; 8NZaXti0o9n7a3l5 - 001 (M.-W.W); National Natural Science Foundation of China grants 21704064 (Q.Z.), 81573479 M0e0g1a (RM&.-DW P.Wro)g; rNamat ifoonr aDl rNuga tDuriascl oSvceireyn cgeraFnotus n2d01a8tiZoXn 0o9f71C1h0i0n2a-0g0r2a-0n0ts5 2(D17.Y04.)0a6n4d ( Q20.Z18.)Z, X80195773354-79 (D.Y.), 81773792 (D.Y.), 81872915 (M.-W.W.), 82073904 (M.-W.W.) and 31971178 (S.Z.); Shanghai Sci-00(1D .(YM.).,-8W17.W73)7; 9N2 a(Dtio.Yn.a),l 8N18a7tu29ra1l5 S(Mcie.-nWce.WF.o)u, 8n2d0a7t3io9n04 o (fMC.-hWin.Wa .g)raanndts 3 12917710147086 4(S (.QZ..)Z; .S)h, a8n1g57h3a4i 7S9c i-ence & Technology Development Fund grant 16ZR1407100 (A.D.); Novo Nordisk-CAS Research (De.nYc.e), &81 7T7e3c7h9n2o (lDog.Yy. )D, 8e1v8e7l2o9p1m5 e(nMt .-FWun.Wd .g),r 8a2n0t7 1369Z04R (1M40.7-W10.0W (.A) a.Dnd.) ;3 N19o7v1o17N8 o(Srd.Zis.)k; -SChAanSg Rheasi eSacric-h Fund grant NNCAS-2017-1-CC (D.Y.) and annual overhead support from ShanghaiTech University enFcuen &d gTreacnhtn NoNloCgyA SD-e2v01e7lo-1p-mCeCn (tD F.uYn.)d a ngdra antn 1u6aZl Rov14e0rh71ea0d0 s(Aup.Dp.o);r tN froovmo SNhoarndgihska-iTCeAcSh URensievaerrcshit y and Chinese Academy of Sciences. Fuanndd gCrhainnte NseN ACcAadSe-2m0y1 7o-f1 -SCciCe n(Dce.sY. .) and annual overhead support from ShanghaiTech University Funding: This research was partially supported by National Key Research and Development Program of China grants 2018YFA0507000 (S.Z. and M.-W.W.) and 2016YFC0905900 (S.Z.); National Mega R&D Program for Drug Discovery grants 2018ZX09711002-002-005 (D.Y.) and 2018ZX09735-001 (M.-W.W); National Natural Science Foundation of China grants 21704064 (Q.Z.), 81573479 (D.Y.), 81773792 (D.Y.), 81872915 (M.-W.W.), 82073904 (M.-W.W.) and 31971178 (S.Z.); Shanghai Science & Technology Development Fund grant 16ZR1407100 (A.D.); Novo Nordisk-CAS Research Fund grant NNCAS-2017-1-CC (D.Y.) and annual overhead support from ShanghaiTech University and Chinese Academy of Sciences.

Funders	Funder number
National Mega R&D Program for Drug Discovery	2018ZX09735-001, 2018ZX09711002-002-005
Novo Nordisk-CAS Research	8e1v8e7l2o9p1m5
Novo Nordisk-CAS Research Fund	NNCAS-2017-1-CC
ShanghaiTech University enFcuen
Shanghai Science and Technology Development Foundation
National Natural Science Foundation of China	21704064, 31971178, 81872915, 16ZR1407100, 81773792, 82073904, 81573479 M0e0g1a
Chinese Academy of Sciences
National Key Research and Development Program of China	2016YFC0905900, 2018YFA0507000
ShanghaiTech University

Keywords

Allosteric modulator
Drug discovery
GLP-1R
Molecular docking
Virtual screening

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.3390/biom11070929

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@article{fd3927d412c848d2b0292eb660ab1e69,

title = "Discovery of novel allosteric modulators targeting an extra-helical binding site of glp-1r using structure-and ligand-based virtual screening",

abstract = "Allosteric modulators have emerged with many potential pharmacological advantages as they do not compete the binding of agonist or antagonist to the orthosteric sites but ultimately affect downstream signaling. To identify allosteric modulators targeting an extra-helical binding site of the glucagon-like peptide-1 receptor (GLP-1R) within the membrane environment, the following two computational approaches were applied: structure-based virtual screening with consideration of lipid contacts and ligand-based virtual screening with the maintenance of specific allosteric pocket residue interactions. Verified by radiolabeled ligand binding and cAMP accumulation experiments, two negative allosteric modulators and seven positive allosteric modulators were discovered using structure-based and ligand-based virtual screening methods, respectively. The computational approach presented here could possibly be used to discover allosteric modulators of other G protein-coupled receptors.",

keywords = "Allosteric modulator, Drug discovery, GLP-1R, Molecular docking, Virtual screening",

author = "Qingtong Zhou and Wanjing Guo and Antao Dai and Xiaoqing Cai and M{\'a}rton Vass and {de Graaf}, Chris and Wenqing Shui and Suwen Zhao and Dehua Yang and Wang, {Ming Wei}",

note = "Funding Information: sFcurinpdt.ing: This research was partially supported by National Key Research and Development Pro-Funding: This research was partially supported by National Key Research and Development Program of China grants 2018YFA0507000 (S.Z. and M.-W.W.) and 2016YFC0905900 (S.Z.); National Fugnradmin go:f TChhiisnrae sgeraarncths w20a1s8 pYaFrAti0a5ll0y70su00p p(So.rZte. da nbdy MNa.-tWion.Wal.)KaenydR 2e0s1e6aYrcFhC a0n9d05D90e0v e(lSo.pZm.);e Nnta Ptiroon-al Mega R&D Program for Drug Discovery grants 2018ZX09711002-002-005 (D.Y.) and 2018ZX09735-grMameg ao fR C&hDin Par gograrnamts 2fo0r1 8DYrFuAg 0D5i0s7c0o0v0e r(yS .gZr. aanntds 2M01.-8WZX.W09.)71a1n0d0 22-001062Y-0F0C50 (9D0.5Y9.0)0a n(Sd. Z2.0)1; 8NZaXti0o9n7a3l5 - 001 (M.-W.W); National Natural Science Foundation of China grants 21704064 (Q.Z.), 81573479 M0e0g1a (RM&.-DW P.Wro)g; rNamat ifoonr aDl rNuga tDuriascl oSvceireyn cgeraFnotus n2d01a8tiZoXn 0o9f71C1h0i0n2a-0g0r2a-0n0ts5 2(D17.Y04.)0a6n4d ( Q20.Z18.)Z, X80195773354-79 (D.Y.), 81773792 (D.Y.), 81872915 (M.-W.W.), 82073904 (M.-W.W.) and 31971178 (S.Z.); Shanghai Sci-00(1D .(YM.).,-8W17.W73)7; 9N2 a(Dtio.Yn.a),l 8N18a7tu29ra1l5 S(Mcie.-nWce.WF.o)u, 8n2d0a7t3io9n04 o (fMC.-hWin.Wa .g)raanndts 3 12917710147086 4(S (.QZ..)Z; .S)h, a8n1g57h3a4i 7S9c i-ence & Technology Development Fund grant 16ZR1407100 (A.D.); Novo Nordisk-CAS Research (De.nYc.e), &81 7T7e3c7h9n2o (lDog.Yy. )D, 8e1v8e7l2o9p1m5 e(nMt .-FWun.Wd .g),r 8a2n0t7 1369Z04R (1M40.7-W10.0W (.A) a.Dnd.) ;3 N19o7v1o17N8 o(Srd.Zis.)k; -SChAanSg Rheasi eSacric-h Fund grant NNCAS-2017-1-CC (D.Y.) and annual overhead support from ShanghaiTech University enFcuen &d gTreacnhtn NoNloCgyA SD-e2v01e7lo-1p-mCeCn (tD F.uYn.)d a ngdra antn 1u6aZl Rov14e0rh71ea0d0 s(Aup.Dp.o);r tN froovmo SNhoarndgihska-iTCeAcSh URensievaerrcshit y and Chinese Academy of Sciences. Fuanndd gCrhainnte NseN ACcAadSe-2m0y1 7o-f1 -SCciCe n(Dce.sY. .) and annual overhead support from ShanghaiTech University Funding Information: Funding: This research was partially supported by National Key Research and Development Program of China grants 2018YFA0507000 (S.Z. and M.-W.W.) and 2016YFC0905900 (S.Z.); National Mega R&D Program for Drug Discovery grants 2018ZX09711002-002-005 (D.Y.) and 2018ZX09735-001 (M.-W.W); National Natural Science Foundation of China grants 21704064 (Q.Z.), 81573479 (D.Y.), 81773792 (D.Y.), 81872915 (M.-W.W.), 82073904 (M.-W.W.) and 31971178 (S.Z.); Shanghai Science & Technology Development Fund grant 16ZR1407100 (A.D.); Novo Nordisk-CAS Research Fund grant NNCAS-2017-1-CC (D.Y.) and annual overhead support from ShanghaiTech University and Chinese Academy of Sciences. Publisher Copyright: {\textcopyright} 2021 by the authors. Licensee MDPI, Basel, Switzerland. Copyright: Copyright 2021 Elsevier B.V., All rights reserved.",

year = "2021",

month = jul,

doi = "10.3390/biom11070929",

language = "English",

volume = "11",

journal = "Biomolecules",

issn = "2218-273X",

publisher = "Multidisciplinary Digital Publishing Institute (MDPI)",

number = "7",

}

TY - JOUR

T1 - Discovery of novel allosteric modulators targeting an extra-helical binding site of glp-1r using structure-and ligand-based virtual screening

AU - Zhou, Qingtong

AU - Guo, Wanjing

AU - Dai, Antao

AU - Cai, Xiaoqing

AU - Vass, Márton

AU - de Graaf, Chris

AU - Shui, Wenqing

AU - Zhao, Suwen

AU - Yang, Dehua

AU - Wang, Ming Wei

N1 - Funding Information: sFcurinpdt.ing: This research was partially supported by National Key Research and Development Pro-Funding: This research was partially supported by National Key Research and Development Program of China grants 2018YFA0507000 (S.Z. and M.-W.W.) and 2016YFC0905900 (S.Z.); National Fugnradmin go:f TChhiisnrae sgeraarncths w20a1s8 pYaFrAti0a5ll0y70su00p p(So.rZte. da nbdy MNa.-tWion.Wal.)KaenydR 2e0s1e6aYrcFhC a0n9d05D90e0v e(lSo.pZm.);e Nnta Ptiroon-al Mega R&D Program for Drug Discovery grants 2018ZX09711002-002-005 (D.Y.) and 2018ZX09735-grMameg ao fR C&hDin Par gograrnamts 2fo0r1 8DYrFuAg 0D5i0s7c0o0v0e r(yS .gZr. aanntds 2M01.-8WZX.W09.)71a1n0d0 22-001062Y-0F0C50 (9D0.5Y9.0)0a n(Sd. Z2.0)1; 8NZaXti0o9n7a3l5 - 001 (M.-W.W); National Natural Science Foundation of China grants 21704064 (Q.Z.), 81573479 M0e0g1a (RM&.-DW P.Wro)g; rNamat ifoonr aDl rNuga tDuriascl oSvceireyn cgeraFnotus n2d01a8tiZoXn 0o9f71C1h0i0n2a-0g0r2a-0n0ts5 2(D17.Y04.)0a6n4d ( Q20.Z18.)Z, X80195773354-79 (D.Y.), 81773792 (D.Y.), 81872915 (M.-W.W.), 82073904 (M.-W.W.) and 31971178 (S.Z.); Shanghai Sci-00(1D .(YM.).,-8W17.W73)7; 9N2 a(Dtio.Yn.a),l 8N18a7tu29ra1l5 S(Mcie.-nWce.WF.o)u, 8n2d0a7t3io9n04 o (fMC.-hWin.Wa .g)raanndts 3 12917710147086 4(S (.QZ..)Z; .S)h, a8n1g57h3a4i 7S9c i-ence & Technology Development Fund grant 16ZR1407100 (A.D.); Novo Nordisk-CAS Research (De.nYc.e), &81 7T7e3c7h9n2o (lDog.Yy. )D, 8e1v8e7l2o9p1m5 e(nMt .-FWun.Wd .g),r 8a2n0t7 1369Z04R (1M40.7-W10.0W (.A) a.Dnd.) ;3 N19o7v1o17N8 o(Srd.Zis.)k; -SChAanSg Rheasi eSacric-h Fund grant NNCAS-2017-1-CC (D.Y.) and annual overhead support from ShanghaiTech University enFcuen &d gTreacnhtn NoNloCgyA SD-e2v01e7lo-1p-mCeCn (tD F.uYn.)d a ngdra antn 1u6aZl Rov14e0rh71ea0d0 s(Aup.Dp.o);r tN froovmo SNhoarndgihska-iTCeAcSh URensievaerrcshit y and Chinese Academy of Sciences. Fuanndd gCrhainnte NseN ACcAadSe-2m0y1 7o-f1 -SCciCe n(Dce.sY. .) and annual overhead support from ShanghaiTech University Funding Information: Funding: This research was partially supported by National Key Research and Development Program of China grants 2018YFA0507000 (S.Z. and M.-W.W.) and 2016YFC0905900 (S.Z.); National Mega R&D Program for Drug Discovery grants 2018ZX09711002-002-005 (D.Y.) and 2018ZX09735-001 (M.-W.W); National Natural Science Foundation of China grants 21704064 (Q.Z.), 81573479 (D.Y.), 81773792 (D.Y.), 81872915 (M.-W.W.), 82073904 (M.-W.W.) and 31971178 (S.Z.); Shanghai Science & Technology Development Fund grant 16ZR1407100 (A.D.); Novo Nordisk-CAS Research Fund grant NNCAS-2017-1-CC (D.Y.) and annual overhead support from ShanghaiTech University and Chinese Academy of Sciences. Publisher Copyright: © 2021 by the authors. Licensee MDPI, Basel, Switzerland. Copyright: Copyright 2021 Elsevier B.V., All rights reserved.

PY - 2021/7

Y1 - 2021/7

N2 - Allosteric modulators have emerged with many potential pharmacological advantages as they do not compete the binding of agonist or antagonist to the orthosteric sites but ultimately affect downstream signaling. To identify allosteric modulators targeting an extra-helical binding site of the glucagon-like peptide-1 receptor (GLP-1R) within the membrane environment, the following two computational approaches were applied: structure-based virtual screening with consideration of lipid contacts and ligand-based virtual screening with the maintenance of specific allosteric pocket residue interactions. Verified by radiolabeled ligand binding and cAMP accumulation experiments, two negative allosteric modulators and seven positive allosteric modulators were discovered using structure-based and ligand-based virtual screening methods, respectively. The computational approach presented here could possibly be used to discover allosteric modulators of other G protein-coupled receptors.

AB - Allosteric modulators have emerged with many potential pharmacological advantages as they do not compete the binding of agonist or antagonist to the orthosteric sites but ultimately affect downstream signaling. To identify allosteric modulators targeting an extra-helical binding site of the glucagon-like peptide-1 receptor (GLP-1R) within the membrane environment, the following two computational approaches were applied: structure-based virtual screening with consideration of lipid contacts and ligand-based virtual screening with the maintenance of specific allosteric pocket residue interactions. Verified by radiolabeled ligand binding and cAMP accumulation experiments, two negative allosteric modulators and seven positive allosteric modulators were discovered using structure-based and ligand-based virtual screening methods, respectively. The computational approach presented here could possibly be used to discover allosteric modulators of other G protein-coupled receptors.

KW - Allosteric modulator

KW - Drug discovery

KW - GLP-1R

KW - Molecular docking

KW - Virtual screening

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UR - http://www.scopus.com/inward/citedby.url?scp=85108221141&partnerID=8YFLogxK

U2 - 10.3390/biom11070929

DO - 10.3390/biom11070929

M3 - Article

AN - SCOPUS:85108221141

SN - 2218-273X

VL - 11

JO - Biomolecules

JF - Biomolecules

IS - 7

M1 - 929

ER -

Discovery of novel allosteric modulators targeting an extra-helical binding site of glp-1r using structure-and ligand-based virtual screening

Abstract

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UN SDGs

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