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.
N1 - Funding Information:
This work was supported by grants from the National Science Center (SONATA funding), Poland [grant number UMO-2013/09/D/NZ7/04549] to K.T-D. (PI) and H.R.A. (Co-PI); California Northstate University College of Medicine, USA (to H.R.A.). Calculations were partially performed under a computational grant (G30-18) and grant on the supercomputer OKEANOS (GA69-29), both provided by the Interdisciplinary Center for Mathematical and Computational Modeling (ICM), Warsaw, Poland, and under resources and licenses from CSC, Finland (to A.K).
Funding Information:
This work was supported by grants from the National Science Center (SONATA funding), Poland [grant number UMO-2013/ 09/D/NZ7/04549] to K.T-D. (PI) and H.R.A. (Co-PI); California Northstate University College of Medicine, USA (to H.R.A.). Calculations were partially performed under a computational grant (G30-18) and grant on the supercomputer OKEA- NOS (GA69-29), both provided by the Interdisciplinary Center for Mathematical and Computational Modeling (ICM), Warsaw, Poland, and under resources and licenses from CSC, Finland (to A.K).
Publisher Copyright:
© 2018, © 2018 Informa UK Limited, trading as Taylor & Francis Group.
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
SN - 0739-1102
VL - 37
SP - 411
EP - 439
JO - Journal of Biomolecular Structure and Dynamics
JF - Journal of Biomolecular Structure and Dynamics
IS - 2
ER -