Reaction profiling of a set of acrylamide-based human tissue transglutaminase inhibitors

Mahmood Jasim, Daniel L Rathbone

Research output: Contribution to journalArticle

Abstract

The major function of the enzyme human tissue transglutaminase (TG2) is the crosslinking of proteins via a transamidation between the γ-carboxamide of a glutamine and the ε-amino group of a lysine. Overexpression of TG2 can lead to undesirable outcomes and has been linked to conditions such as fibrosis, celiac disease and neurodegenerative diseases. Accordingly, TG2 is a tempting drug target. The most effective TG2 inhibitors to date are small-molecule peptidomimetics featuring electrophilic warheads that irreversibly modify the active site catalytic cysteine (CYS277). In an effort to facilitate the design of such TG2 inhibitors, we undertook a quantum mechanical reaction profiling of the Michael reaction between a set of six acrylamide-based known TG2 inhibitors and the TG2 CYS277. The inhibitors were docked into the active site and the coordinates were refined by MD simulations prior to modelling the covalent modification of the CYS277 thiolate. The results of QM/MM MD umbrella sampling applied to reaction coordinates driving the Michael reaction are presented for two approximations of the Michael reaction: a concerted reaction (simultaneous thiolate attack onto the acrylamide warhead and pronation from the adjacent HIS335) and a two-stage reaction (consecutive thiolate attack and protonation). The two-stage approximation of the Michael reaction gave the better results for the evaluation of acrylamide-based potential TG2 inhibitors in silico. Good correlations were observed between the experimental TG2 IC50 data and the calculated activation energies over the range 0.0061 – 6.3 µM (three orders of magnitude) and we propose that this approach may be used to evaluate acrylamide-based potential TG2 inhibitors.
LanguageEnglish
Pages157-165
Number of pages9
JournalJournal of Molecular Graphics and Modelling
Volume79
Early online date22 Nov 2017
DOIs
Publication statusPublished - 1 Jan 2018

Fingerprint

Neurodegenerative diseases
Acrylamide
Protonation
Michael reaction
Crosslinking
inhibitors
Enzymes
Activation energy
Tissue
Sampling
Proteins
Molecules
warheads
Peptidomimetics
attack
Glutamine
Lysine
glutamine
Cysteine
fibrosis

Bibliographical note

© The Authors. Published by Elsevier Inc. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

Funding: Iraqi Ministry of Higher Education and Scientific Research.

Keywords

  • Tissue transglutaminase
  • Irreversible inhibitors
  • Molecular docking
  • Molecular dynamics
  • Umbrella sampling

Cite this

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title = "Reaction profiling of a set of acrylamide-based human tissue transglutaminase inhibitors",
abstract = "The major function of the enzyme human tissue transglutaminase (TG2) is the crosslinking of proteins via a transamidation between the γ-carboxamide of a glutamine and the ε-amino group of a lysine. Overexpression of TG2 can lead to undesirable outcomes and has been linked to conditions such as fibrosis, celiac disease and neurodegenerative diseases. Accordingly, TG2 is a tempting drug target. The most effective TG2 inhibitors to date are small-molecule peptidomimetics featuring electrophilic warheads that irreversibly modify the active site catalytic cysteine (CYS277). In an effort to facilitate the design of such TG2 inhibitors, we undertook a quantum mechanical reaction profiling of the Michael reaction between a set of six acrylamide-based known TG2 inhibitors and the TG2 CYS277. The inhibitors were docked into the active site and the coordinates were refined by MD simulations prior to modelling the covalent modification of the CYS277 thiolate. The results of QM/MM MD umbrella sampling applied to reaction coordinates driving the Michael reaction are presented for two approximations of the Michael reaction: a concerted reaction (simultaneous thiolate attack onto the acrylamide warhead and pronation from the adjacent HIS335) and a two-stage reaction (consecutive thiolate attack and protonation). The two-stage approximation of the Michael reaction gave the better results for the evaluation of acrylamide-based potential TG2 inhibitors in silico. Good correlations were observed between the experimental TG2 IC50 data and the calculated activation energies over the range 0.0061 – 6.3 µM (three orders of magnitude) and we propose that this approach may be used to evaluate acrylamide-based potential TG2 inhibitors.",
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Reaction profiling of a set of acrylamide-based human tissue transglutaminase inhibitors. / Jasim, Mahmood; Rathbone, Daniel L.

In: Journal of Molecular Graphics and Modelling , Vol. 79, 01.01.2018, p. 157-165.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Reaction profiling of a set of acrylamide-based human tissue transglutaminase inhibitors

AU - Jasim, Mahmood

AU - Rathbone, Daniel L

N1 - © The Authors. Published by Elsevier Inc. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). Funding: Iraqi Ministry of Higher Education and Scientific Research.

PY - 2018/1/1

Y1 - 2018/1/1

N2 - The major function of the enzyme human tissue transglutaminase (TG2) is the crosslinking of proteins via a transamidation between the γ-carboxamide of a glutamine and the ε-amino group of a lysine. Overexpression of TG2 can lead to undesirable outcomes and has been linked to conditions such as fibrosis, celiac disease and neurodegenerative diseases. Accordingly, TG2 is a tempting drug target. The most effective TG2 inhibitors to date are small-molecule peptidomimetics featuring electrophilic warheads that irreversibly modify the active site catalytic cysteine (CYS277). In an effort to facilitate the design of such TG2 inhibitors, we undertook a quantum mechanical reaction profiling of the Michael reaction between a set of six acrylamide-based known TG2 inhibitors and the TG2 CYS277. The inhibitors were docked into the active site and the coordinates were refined by MD simulations prior to modelling the covalent modification of the CYS277 thiolate. The results of QM/MM MD umbrella sampling applied to reaction coordinates driving the Michael reaction are presented for two approximations of the Michael reaction: a concerted reaction (simultaneous thiolate attack onto the acrylamide warhead and pronation from the adjacent HIS335) and a two-stage reaction (consecutive thiolate attack and protonation). The two-stage approximation of the Michael reaction gave the better results for the evaluation of acrylamide-based potential TG2 inhibitors in silico. Good correlations were observed between the experimental TG2 IC50 data and the calculated activation energies over the range 0.0061 – 6.3 µM (three orders of magnitude) and we propose that this approach may be used to evaluate acrylamide-based potential TG2 inhibitors.

AB - The major function of the enzyme human tissue transglutaminase (TG2) is the crosslinking of proteins via a transamidation between the γ-carboxamide of a glutamine and the ε-amino group of a lysine. Overexpression of TG2 can lead to undesirable outcomes and has been linked to conditions such as fibrosis, celiac disease and neurodegenerative diseases. Accordingly, TG2 is a tempting drug target. The most effective TG2 inhibitors to date are small-molecule peptidomimetics featuring electrophilic warheads that irreversibly modify the active site catalytic cysteine (CYS277). In an effort to facilitate the design of such TG2 inhibitors, we undertook a quantum mechanical reaction profiling of the Michael reaction between a set of six acrylamide-based known TG2 inhibitors and the TG2 CYS277. The inhibitors were docked into the active site and the coordinates were refined by MD simulations prior to modelling the covalent modification of the CYS277 thiolate. The results of QM/MM MD umbrella sampling applied to reaction coordinates driving the Michael reaction are presented for two approximations of the Michael reaction: a concerted reaction (simultaneous thiolate attack onto the acrylamide warhead and pronation from the adjacent HIS335) and a two-stage reaction (consecutive thiolate attack and protonation). The two-stage approximation of the Michael reaction gave the better results for the evaluation of acrylamide-based potential TG2 inhibitors in silico. Good correlations were observed between the experimental TG2 IC50 data and the calculated activation energies over the range 0.0061 – 6.3 µM (three orders of magnitude) and we propose that this approach may be used to evaluate acrylamide-based potential TG2 inhibitors.

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KW - Molecular dynamics

KW - Umbrella sampling

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