Aryl Sulfonamide Inhibitors of Insulin-Regulated Aminopeptidase Enhance Spine Density in Primary Hippocampal Neuron Cultures

Shanti Diwakarla, Erik Nylander, Alfhild Grönbladh, Sudarsana Reddy Vanga, Yasmin Shamsudin Khan, Hugo Gutiérrez-De-Terán, Jonas Sävmarker, Leelee Ng, Vi Pham, Thomas Lundbäck, Annika Jenmalm-Jensen, Richard Svensson, Per Artursson, Sofia Zelleroth, Karin Engen, Ulrika Rosenström, Mats Larhed, Johan Åqvist, Siew Yeen Chai, Mathias Hallberg

Research output: Contribution to journalArticleResearchpeer-review

10 Citations (Scopus)

Abstract

The zinc metallopeptidase insulin regulated aminopeptidase (IRAP), which is highly expressed in the hippocampus and other brain regions associated with cognitive function, has been identified as a high-affinity binding site of the hexapeptide angiotensin IV (Ang IV). This hexapeptide is thought to facilitate learning and memory by binding to the catalytic site of IRAP to inhibit its enzymatic activity. In support of this hypothesis, low molecular weight, nonpeptide specific inhibitors of IRAP have been shown to enhance memory in rodent models. Recently, it was demonstrated that linear and macrocyclic Ang IV-derived peptides can alter the shape and increase the number of dendritic spines in hippocampal cultures, properties associated with enhanced cognitive performance. After screening a library of 10 500 drug-like substances for their ability to inhibit IRAP, we identified a series of low molecular weight aryl sulfonamides, which exhibit no structural similarity to Ang IV, as moderately potent IRAP inhibitors. A structural and biological characterization of three of these aryl sulfonamides was performed. Their binding modes to human IRAP were explored by docking calculations combined with molecular dynamics simulations and binding affinity estimations using the linear interaction energy method. Two alternative binding modes emerged from this analysis, both of which correctly rank the ligands according to their experimental binding affinities for this series of compounds. Finally, we show that two of these drug-like IRAP inhibitors can alter dendritic spine morphology and increase spine density in primary cultures of hippocampal neurons.

Original languageEnglish
Pages (from-to)1383-1392
Number of pages10
JournalACS Chemical Neuroscience
Volume7
Issue number10
DOIs
Publication statusPublished - 19 Oct 2016

Keywords

  • aryl sulfonamides
  • dendritic spines
  • hippocampal neurons
  • Insulin-regulated aminopeptidase
  • ligand interaction energy simulations
  • molecular dynamics

Cite this

Diwakarla, S., Nylander, E., Grönbladh, A., Vanga, S. R., Khan, Y. S., Gutiérrez-De-Terán, H., ... Hallberg, M. (2016). Aryl Sulfonamide Inhibitors of Insulin-Regulated Aminopeptidase Enhance Spine Density in Primary Hippocampal Neuron Cultures. ACS Chemical Neuroscience, 7(10), 1383-1392. https://doi.org/10.1021/acschemneuro.6b00146
Diwakarla, Shanti ; Nylander, Erik ; Grönbladh, Alfhild ; Vanga, Sudarsana Reddy ; Khan, Yasmin Shamsudin ; Gutiérrez-De-Terán, Hugo ; Sävmarker, Jonas ; Ng, Leelee ; Pham, Vi ; Lundbäck, Thomas ; Jenmalm-Jensen, Annika ; Svensson, Richard ; Artursson, Per ; Zelleroth, Sofia ; Engen, Karin ; Rosenström, Ulrika ; Larhed, Mats ; Åqvist, Johan ; Chai, Siew Yeen ; Hallberg, Mathias. / Aryl Sulfonamide Inhibitors of Insulin-Regulated Aminopeptidase Enhance Spine Density in Primary Hippocampal Neuron Cultures. In: ACS Chemical Neuroscience. 2016 ; Vol. 7, No. 10. pp. 1383-1392.
@article{0bc1c19a37ae446fb526ab43cc56416e,
title = "Aryl Sulfonamide Inhibitors of Insulin-Regulated Aminopeptidase Enhance Spine Density in Primary Hippocampal Neuron Cultures",
abstract = "The zinc metallopeptidase insulin regulated aminopeptidase (IRAP), which is highly expressed in the hippocampus and other brain regions associated with cognitive function, has been identified as a high-affinity binding site of the hexapeptide angiotensin IV (Ang IV). This hexapeptide is thought to facilitate learning and memory by binding to the catalytic site of IRAP to inhibit its enzymatic activity. In support of this hypothesis, low molecular weight, nonpeptide specific inhibitors of IRAP have been shown to enhance memory in rodent models. Recently, it was demonstrated that linear and macrocyclic Ang IV-derived peptides can alter the shape and increase the number of dendritic spines in hippocampal cultures, properties associated with enhanced cognitive performance. After screening a library of 10 500 drug-like substances for their ability to inhibit IRAP, we identified a series of low molecular weight aryl sulfonamides, which exhibit no structural similarity to Ang IV, as moderately potent IRAP inhibitors. A structural and biological characterization of three of these aryl sulfonamides was performed. Their binding modes to human IRAP were explored by docking calculations combined with molecular dynamics simulations and binding affinity estimations using the linear interaction energy method. Two alternative binding modes emerged from this analysis, both of which correctly rank the ligands according to their experimental binding affinities for this series of compounds. Finally, we show that two of these drug-like IRAP inhibitors can alter dendritic spine morphology and increase spine density in primary cultures of hippocampal neurons.",
keywords = "aryl sulfonamides, dendritic spines, hippocampal neurons, Insulin-regulated aminopeptidase, ligand interaction energy simulations, molecular dynamics",
author = "Shanti Diwakarla and Erik Nylander and Alfhild Gr{\"o}nbladh and Vanga, {Sudarsana Reddy} and Khan, {Yasmin Shamsudin} and Hugo Guti{\'e}rrez-De-Ter{\'a}n and Jonas S{\"a}vmarker and Leelee Ng and Vi Pham and Thomas Lundb{\"a}ck and Annika Jenmalm-Jensen and Richard Svensson and Per Artursson and Sofia Zelleroth and Karin Engen and Ulrika Rosenstr{\"o}m and Mats Larhed and Johan {\AA}qvist and Chai, {Siew Yeen} and Mathias Hallberg",
year = "2016",
month = "10",
day = "19",
doi = "10.1021/acschemneuro.6b00146",
language = "English",
volume = "7",
pages = "1383--1392",
journal = "ACS Chemical Neuroscience",
issn = "1948-7193",
publisher = "American Chemical Society",
number = "10",

}

Diwakarla, S, Nylander, E, Grönbladh, A, Vanga, SR, Khan, YS, Gutiérrez-De-Terán, H, Sävmarker, J, Ng, L, Pham, V, Lundbäck, T, Jenmalm-Jensen, A, Svensson, R, Artursson, P, Zelleroth, S, Engen, K, Rosenström, U, Larhed, M, Åqvist, J, Chai, SY & Hallberg, M 2016, 'Aryl Sulfonamide Inhibitors of Insulin-Regulated Aminopeptidase Enhance Spine Density in Primary Hippocampal Neuron Cultures', ACS Chemical Neuroscience, vol. 7, no. 10, pp. 1383-1392. https://doi.org/10.1021/acschemneuro.6b00146

Aryl Sulfonamide Inhibitors of Insulin-Regulated Aminopeptidase Enhance Spine Density in Primary Hippocampal Neuron Cultures. / Diwakarla, Shanti; Nylander, Erik; Grönbladh, Alfhild; Vanga, Sudarsana Reddy; Khan, Yasmin Shamsudin; Gutiérrez-De-Terán, Hugo; Sävmarker, Jonas; Ng, Leelee; Pham, Vi; Lundbäck, Thomas; Jenmalm-Jensen, Annika; Svensson, Richard; Artursson, Per; Zelleroth, Sofia; Engen, Karin; Rosenström, Ulrika; Larhed, Mats; Åqvist, Johan; Chai, Siew Yeen; Hallberg, Mathias.

In: ACS Chemical Neuroscience, Vol. 7, No. 10, 19.10.2016, p. 1383-1392.

Research output: Contribution to journalArticleResearchpeer-review

TY - JOUR

T1 - Aryl Sulfonamide Inhibitors of Insulin-Regulated Aminopeptidase Enhance Spine Density in Primary Hippocampal Neuron Cultures

AU - Diwakarla, Shanti

AU - Nylander, Erik

AU - Grönbladh, Alfhild

AU - Vanga, Sudarsana Reddy

AU - Khan, Yasmin Shamsudin

AU - Gutiérrez-De-Terán, Hugo

AU - Sävmarker, Jonas

AU - Ng, Leelee

AU - Pham, Vi

AU - Lundbäck, Thomas

AU - Jenmalm-Jensen, Annika

AU - Svensson, Richard

AU - Artursson, Per

AU - Zelleroth, Sofia

AU - Engen, Karin

AU - Rosenström, Ulrika

AU - Larhed, Mats

AU - Åqvist, Johan

AU - Chai, Siew Yeen

AU - Hallberg, Mathias

PY - 2016/10/19

Y1 - 2016/10/19

N2 - The zinc metallopeptidase insulin regulated aminopeptidase (IRAP), which is highly expressed in the hippocampus and other brain regions associated with cognitive function, has been identified as a high-affinity binding site of the hexapeptide angiotensin IV (Ang IV). This hexapeptide is thought to facilitate learning and memory by binding to the catalytic site of IRAP to inhibit its enzymatic activity. In support of this hypothesis, low molecular weight, nonpeptide specific inhibitors of IRAP have been shown to enhance memory in rodent models. Recently, it was demonstrated that linear and macrocyclic Ang IV-derived peptides can alter the shape and increase the number of dendritic spines in hippocampal cultures, properties associated with enhanced cognitive performance. After screening a library of 10 500 drug-like substances for their ability to inhibit IRAP, we identified a series of low molecular weight aryl sulfonamides, which exhibit no structural similarity to Ang IV, as moderately potent IRAP inhibitors. A structural and biological characterization of three of these aryl sulfonamides was performed. Their binding modes to human IRAP were explored by docking calculations combined with molecular dynamics simulations and binding affinity estimations using the linear interaction energy method. Two alternative binding modes emerged from this analysis, both of which correctly rank the ligands according to their experimental binding affinities for this series of compounds. Finally, we show that two of these drug-like IRAP inhibitors can alter dendritic spine morphology and increase spine density in primary cultures of hippocampal neurons.

AB - The zinc metallopeptidase insulin regulated aminopeptidase (IRAP), which is highly expressed in the hippocampus and other brain regions associated with cognitive function, has been identified as a high-affinity binding site of the hexapeptide angiotensin IV (Ang IV). This hexapeptide is thought to facilitate learning and memory by binding to the catalytic site of IRAP to inhibit its enzymatic activity. In support of this hypothesis, low molecular weight, nonpeptide specific inhibitors of IRAP have been shown to enhance memory in rodent models. Recently, it was demonstrated that linear and macrocyclic Ang IV-derived peptides can alter the shape and increase the number of dendritic spines in hippocampal cultures, properties associated with enhanced cognitive performance. After screening a library of 10 500 drug-like substances for their ability to inhibit IRAP, we identified a series of low molecular weight aryl sulfonamides, which exhibit no structural similarity to Ang IV, as moderately potent IRAP inhibitors. A structural and biological characterization of three of these aryl sulfonamides was performed. Their binding modes to human IRAP were explored by docking calculations combined with molecular dynamics simulations and binding affinity estimations using the linear interaction energy method. Two alternative binding modes emerged from this analysis, both of which correctly rank the ligands according to their experimental binding affinities for this series of compounds. Finally, we show that two of these drug-like IRAP inhibitors can alter dendritic spine morphology and increase spine density in primary cultures of hippocampal neurons.

KW - aryl sulfonamides

KW - dendritic spines

KW - hippocampal neurons

KW - Insulin-regulated aminopeptidase

KW - ligand interaction energy simulations

KW - molecular dynamics

UR - http://www.scopus.com/inward/record.url?scp=84992186834&partnerID=8YFLogxK

U2 - 10.1021/acschemneuro.6b00146

DO - 10.1021/acschemneuro.6b00146

M3 - Article

VL - 7

SP - 1383

EP - 1392

JO - ACS Chemical Neuroscience

JF - ACS Chemical Neuroscience

SN - 1948-7193

IS - 10

ER -