Molecular interactions of type I and type II positive allosteric modulators with the human α7 nicotinic acetylcholine receptor: an in silico study

Katarzyna M. Targowska-Duda, Agnieszka A. Kaczor, Krzysztof Jozwiak, Hugo R. Arias

Research output: Contribution to journalArticle

2 Citations (Scopus)

Abstract

The binding site locations and structural components for type I and type II positive allosteric modulators (PAMs) of the α7 nicotinic acetylcholine receptor (nAChR) have not been fully characterized yet. In this regard, homology models of the human α7 nAChR and hα7/m5-HT 3A chimera, built using the crystal structure of the serotonin type 3A receptor (5-ΗΤ R), were used for molecular docking and molecular dynamics simulations to study the molecular interactions of selected type I (5-hydroxyindol, NS-1738, and LY-2087101) and type II (PNU-120596, PAM-2, and TBS-516) PAMs. The docking results indicate: (1) a site located in the extracellular domain (ECD) for type I PAMs such as NS-1738 and LY-2087101, but not for 5-HI; (2) an overlapping site in the ECD–transmembrane domain (TMD) junction for all studied PAMs. Additional docking results on the hα7/m5-HT 3A chimera supported experimental results indicating that the ECD site might be relevant for type I PAM activity; and (3) two TMD sites, an intrasubunit site that recognizes type II PAMs, and an intersubunit pocket with high specificity for 5-HI (type I PAM). The in silico α7TSLMF mutant results support the view that M1–Ser223 and M3–Ile281 are key residues for the interaction of PAM-2 and PNU-120596 with the intrasubunit cavity. Our in silico results are in agreement with experimental data showing that the intrasubunit cavity is relevant for the activity of type II PAMs, and suggest that the ECD–TMD junction and intersubunit sites could be significant for the activity of type I PAMs.

Original languageEnglish
Pages (from-to)411-439
Number of pages29
JournalJournal of Biomolecular Structure and Dynamics
Volume37
Issue number2
DOIs
StatePublished - 22 Jan 2019
Externally publishedYes

Fingerprint

Nicotinic Receptors
Computer Simulation
Molecular Dynamics Simulation
Binding Sites
1-(5-chloro-2,4-dimethoxyphenyl)-3-(5-methylisoxazol-3-yl)urea
1-(5-chloro-2-hydroxyphenyl)-3-(2-chloro-5-trifluoromethylphenyl)urea
serotonin 5 receptor

Keywords

  • 5-HI: 5-hydroxyindole
  • ACh: acetylcholine
  • AChBP: acetylcholine binding protein
  • ECD: extracellular domain
  • LY-2087101: [2-(4-fluoro-phenylamino)-4-methyl-thiazol-5-yl]-thiophen-3-yl-methanone
  • m5-HT R: murine serotonin type 3A receptor
  • molecular docking
  • molecular dynamics
  • nAChR: nicotinic acetylcholine receptor
  • nicotinic acetylcholine receptor
  • NS-1738: 1-(5-chloro-2-hydroxy-phenyl)-3-(2-chloro-5-trifluoromethyl-phenyl)-urea
  • PAM-2: 3-furan-2-yl-N-p-tolyl-acrylamide
  • PAM: positive allosteric modulator
  • pLGICs: pentameric ligand-gated ion channels
  • PNU-120596: 1-(5-chloro-2,4-dimethoxyphenyl)-3-(5-methyl-isoxazol-3-yl)-urea
  • TBS-516: 4-(5-benzyl-3-(4-bromophenyl)-1H-1,2,4-triazol-1-yl)benzenesulfonamide
  • TMD: transmembrane domain
  • type I and type II positive allosteric modulators
  • α7 PAMs

Cite this

@article{4a48fb2232924c61b0612fe48e91481d,
title = "Molecular interactions of type I and type II positive allosteric modulators with the human α7 nicotinic acetylcholine receptor: an in silico study",
abstract = "The binding site locations and structural components for type I and type II positive allosteric modulators (PAMs) of the α7 nicotinic acetylcholine receptor (nAChR) have not been fully characterized yet. In this regard, homology models of the human α7 nAChR and hα7/m5-HT 3A chimera, built using the crystal structure of the serotonin type 3A receptor (5-ΗΤ 3Α R), were used for molecular docking and molecular dynamics simulations to study the molecular interactions of selected type I (5-hydroxyindol, NS-1738, and LY-2087101) and type II (PNU-120596, PAM-2, and TBS-516) PAMs. The docking results indicate: (1) a site located in the extracellular domain (ECD) for type I PAMs such as NS-1738 and LY-2087101, but not for 5-HI; (2) an overlapping site in the ECD–transmembrane domain (TMD) junction for all studied PAMs. Additional docking results on the hα7/m5-HT 3A chimera supported experimental results indicating that the ECD site might be relevant for type I PAM activity; and (3) two TMD sites, an intrasubunit site that recognizes type II PAMs, and an intersubunit pocket with high specificity for 5-HI (type I PAM). The in silico α7TSLMF mutant results support the view that M1–Ser223 and M3–Ile281 are key residues for the interaction of PAM-2 and PNU-120596 with the intrasubunit cavity. Our in silico results are in agreement with experimental data showing that the intrasubunit cavity is relevant for the activity of type II PAMs, and suggest that the ECD–TMD junction and intersubunit sites could be significant for the activity of type I PAMs.",
keywords = "5-HI: 5-hydroxyindole, ACh: acetylcholine, AChBP: acetylcholine binding protein, ECD: extracellular domain, LY-2087101: [2-(4-fluoro-phenylamino)-4-methyl-thiazol-5-yl]-thiophen-3-yl-methanone, m5-HT R: murine serotonin type 3A receptor, molecular docking, molecular dynamics, nAChR: nicotinic acetylcholine receptor, nicotinic acetylcholine receptor, NS-1738: 1-(5-chloro-2-hydroxy-phenyl)-3-(2-chloro-5-trifluoromethyl-phenyl)-urea, PAM-2: 3-furan-2-yl-N-p-tolyl-acrylamide, PAM: positive allosteric modulator, pLGICs: pentameric ligand-gated ion channels, PNU-120596: 1-(5-chloro-2,4-dimethoxyphenyl)-3-(5-methyl-isoxazol-3-yl)-urea, TBS-516: 4-(5-benzyl-3-(4-bromophenyl)-1H-1,2,4-triazol-1-yl)benzenesulfonamide, TMD: transmembrane domain, type I and type II positive allosteric modulators, α7 PAMs",
author = "Targowska-Duda, {Katarzyna M.} and Kaczor, {Agnieszka A.} and Krzysztof Jozwiak and Arias, {Hugo R.}",
year = "2019",
month = "1",
day = "22",
doi = "10.1080/07391102.2018.1427634",
language = "English",
volume = "37",
pages = "411--439",
journal = "Journal of Biomolecular Structure and Dynamics",
issn = "0739-1102",
number = "2",

}

Molecular interactions of type I and type II positive allosteric modulators with the human α7 nicotinic acetylcholine receptor : an in silico study. / Targowska-Duda, Katarzyna M.; Kaczor, Agnieszka A.; Jozwiak, Krzysztof; Arias, Hugo R.

In: Journal of Biomolecular Structure and Dynamics, Vol. 37, No. 2, 22.01.2019, p. 411-439.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Molecular interactions of type I and type II positive allosteric modulators with the human α7 nicotinic acetylcholine receptor

T2 - an in silico study

AU - Targowska-Duda, Katarzyna M.

AU - Kaczor, Agnieszka A.

AU - Jozwiak, Krzysztof

AU - Arias, Hugo R.

PY - 2019/1/22

Y1 - 2019/1/22

N2 - The binding site locations and structural components for type I and type II positive allosteric modulators (PAMs) of the α7 nicotinic acetylcholine receptor (nAChR) have not been fully characterized yet. In this regard, homology models of the human α7 nAChR and hα7/m5-HT 3A chimera, built using the crystal structure of the serotonin type 3A receptor (5-ΗΤ 3Α R), were used for molecular docking and molecular dynamics simulations to study the molecular interactions of selected type I (5-hydroxyindol, NS-1738, and LY-2087101) and type II (PNU-120596, PAM-2, and TBS-516) PAMs. The docking results indicate: (1) a site located in the extracellular domain (ECD) for type I PAMs such as NS-1738 and LY-2087101, but not for 5-HI; (2) an overlapping site in the ECD–transmembrane domain (TMD) junction for all studied PAMs. Additional docking results on the hα7/m5-HT 3A chimera supported experimental results indicating that the ECD site might be relevant for type I PAM activity; and (3) two TMD sites, an intrasubunit site that recognizes type II PAMs, and an intersubunit pocket with high specificity for 5-HI (type I PAM). The in silico α7TSLMF mutant results support the view that M1–Ser223 and M3–Ile281 are key residues for the interaction of PAM-2 and PNU-120596 with the intrasubunit cavity. Our in silico results are in agreement with experimental data showing that the intrasubunit cavity is relevant for the activity of type II PAMs, and suggest that the ECD–TMD junction and intersubunit sites could be significant for the activity of type I PAMs.

AB - The binding site locations and structural components for type I and type II positive allosteric modulators (PAMs) of the α7 nicotinic acetylcholine receptor (nAChR) have not been fully characterized yet. In this regard, homology models of the human α7 nAChR and hα7/m5-HT 3A chimera, built using the crystal structure of the serotonin type 3A receptor (5-ΗΤ 3Α R), were used for molecular docking and molecular dynamics simulations to study the molecular interactions of selected type I (5-hydroxyindol, NS-1738, and LY-2087101) and type II (PNU-120596, PAM-2, and TBS-516) PAMs. The docking results indicate: (1) a site located in the extracellular domain (ECD) for type I PAMs such as NS-1738 and LY-2087101, but not for 5-HI; (2) an overlapping site in the ECD–transmembrane domain (TMD) junction for all studied PAMs. Additional docking results on the hα7/m5-HT 3A chimera supported experimental results indicating that the ECD site might be relevant for type I PAM activity; and (3) two TMD sites, an intrasubunit site that recognizes type II PAMs, and an intersubunit pocket with high specificity for 5-HI (type I PAM). The in silico α7TSLMF mutant results support the view that M1–Ser223 and M3–Ile281 are key residues for the interaction of PAM-2 and PNU-120596 with the intrasubunit cavity. Our in silico results are in agreement with experimental data showing that the intrasubunit cavity is relevant for the activity of type II PAMs, and suggest that the ECD–TMD junction and intersubunit sites could be significant for the activity of type I PAMs.

KW - 5-HI: 5-hydroxyindole

KW - ACh: acetylcholine

KW - AChBP: acetylcholine binding protein

KW - ECD: extracellular domain

KW - LY-2087101: [2-(4-fluoro-phenylamino)-4-methyl-thiazol-5-yl]-thiophen-3-yl-methanone

KW - m5-HT R: murine serotonin type 3A receptor

KW - molecular docking

KW - molecular dynamics

KW - nAChR: nicotinic acetylcholine receptor

KW - nicotinic acetylcholine receptor

KW - NS-1738: 1-(5-chloro-2-hydroxy-phenyl)-3-(2-chloro-5-trifluoromethyl-phenyl)-urea

KW - PAM-2: 3-furan-2-yl-N-p-tolyl-acrylamide

KW - PAM: positive allosteric modulator

KW - pLGICs: pentameric ligand-gated ion channels

KW - PNU-120596: 1-(5-chloro-2,4-dimethoxyphenyl)-3-(5-methyl-isoxazol-3-yl)-urea

KW - TBS-516: 4-(5-benzyl-3-(4-bromophenyl)-1H-1,2,4-triazol-1-yl)benzenesulfonamide

KW - TMD: transmembrane domain

KW - type I and type II positive allosteric modulators

KW - α7 PAMs

UR - http://www.scopus.com/inward/record.url?scp=85042233480&partnerID=8YFLogxK

U2 - 10.1080/07391102.2018.1427634

DO - 10.1080/07391102.2018.1427634

M3 - Article

C2 - 29363414

AN - SCOPUS:85042233480

VL - 37

SP - 411

EP - 439

JO - Journal of Biomolecular Structure and Dynamics

JF - Journal of Biomolecular Structure and Dynamics

SN - 0739-1102

IS - 2

ER -