Chemoproteomic, biochemical and pharmacological approaches in the discovery of inhibitors targeting human α/β-hydrolase domain containing 11 (ABHD11)

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Chemoproteomic, biochemical and pharmacological approaches in the discovery of inhibitors targeting human α/β-hydrolase domain containing 11 (ABHD11). / Navia-Paldanius, Dina; Patel, Jayendra Z.; López Navarro, Miriam; Jakupović, Hermina; Goffart, Steffi; Pasonen-Seppänen, Sanna; Nevalainen, Tapio J.; Jääskeläinen, Tiina; Laitinen, Tuomo; Laitinen, Jarmo T.; Savinainen, Juha R.

In: European Journal of Pharmaceutical Sciences, Vol. 93, 10.10.2016, p. 253-263.

Research output: Contribution to journalJournal articleResearchpeer-review

Harvard

Navia-Paldanius, D, Patel, JZ, López Navarro, M, Jakupović, H, Goffart, S, Pasonen-Seppänen, S, Nevalainen, TJ, Jääskeläinen, T, Laitinen, T, Laitinen, JT & Savinainen, JR 2016, 'Chemoproteomic, biochemical and pharmacological approaches in the discovery of inhibitors targeting human α/β-hydrolase domain containing 11 (ABHD11)', European Journal of Pharmaceutical Sciences, vol. 93, pp. 253-263. https://doi.org/10.1016/j.ejps.2016.08.031

APA

Navia-Paldanius, D., Patel, J. Z., López Navarro, M., Jakupović, H., Goffart, S., Pasonen-Seppänen, S., Nevalainen, T. J., Jääskeläinen, T., Laitinen, T., Laitinen, J. T., & Savinainen, J. R. (2016). Chemoproteomic, biochemical and pharmacological approaches in the discovery of inhibitors targeting human α/β-hydrolase domain containing 11 (ABHD11). European Journal of Pharmaceutical Sciences, 93, 253-263. https://doi.org/10.1016/j.ejps.2016.08.031

Vancouver

Navia-Paldanius D, Patel JZ, López Navarro M, Jakupović H, Goffart S, Pasonen-Seppänen S et al. Chemoproteomic, biochemical and pharmacological approaches in the discovery of inhibitors targeting human α/β-hydrolase domain containing 11 (ABHD11). European Journal of Pharmaceutical Sciences. 2016 Oct 10;93:253-263. https://doi.org/10.1016/j.ejps.2016.08.031

Author

Navia-Paldanius, Dina ; Patel, Jayendra Z. ; López Navarro, Miriam ; Jakupović, Hermina ; Goffart, Steffi ; Pasonen-Seppänen, Sanna ; Nevalainen, Tapio J. ; Jääskeläinen, Tiina ; Laitinen, Tuomo ; Laitinen, Jarmo T. ; Savinainen, Juha R. / Chemoproteomic, biochemical and pharmacological approaches in the discovery of inhibitors targeting human α/β-hydrolase domain containing 11 (ABHD11). In: European Journal of Pharmaceutical Sciences. 2016 ; Vol. 93. pp. 253-263.

Bibtex

@article{9fd677b4b0d14b248272e9591c1148f8,
title = "Chemoproteomic, biochemical and pharmacological approaches in the discovery of inhibitors targeting human α/β-hydrolase domain containing 11 (ABHD11)",
abstract = "ABHD11 (α/β-hydrolase domain containing 11) is a non-annotated enzyme belonging to the family of metabolic serine hydrolases (mSHs). Its natural substrates and products are unknown. Using competitive activity-based protein profiling (ABPP) to identify novel inhibitors of human (h)ABHD11, three compounds from our chemical library exhibited low nanomolar potency towards hABHD11. Competitive ABPP of various proteomes revealed fatty acid amide hydrolase (FAAH) as the sole off-target among the mSHs. Our fluorescent activity assays designed for natural lipase substrates revealed no activity of hABHD11 towards mono- or diacylglycerols. A broader profiling using para-nitrophenyl (pNP)-linked substrates indicated no amidase/protease, phosphatase, sulfatase, phospholipase C or phosphodiesterase activity. Instead, hABHD11 readily utilized para-nitrophenyl butyrate (pNPC4), indicating lipase/esterase-type activity that could be exploited in inhibitor discovery. Additionally, a homology model was created based on the crystal structure of bacterial esterase YbfF. In contrast to YbfF, which reportedly hydrolyze long-chain acyl-CoA, hABHD11 did not utilize oleoyl-CoA or arachidonoyl-CoA. In conclusion, the present study reports the discovery of potent hABHD11 inhibitors with good selectivity among mSHs. We developed substrate-based activity assays for hABHD11 that could be further exploited in inhibitor discovery and created the first homology-based hABHD11 model, offering initial insights into the active site of this poorly characterized enzyme.",
keywords = "ABHD11, ABPP, AFMID, Homology modelling, Inhibitor screening, LYPLA2, Serine hydrolases",
author = "Dina Navia-Paldanius and Patel, {Jayendra Z.} and {L{\'o}pez Navarro}, Miriam and Hermina Jakupovi{\'c} and Steffi Goffart and Sanna Pasonen-Sepp{\"a}nen and Nevalainen, {Tapio J.} and Tiina J{\"a}{\"a}skel{\"a}inen and Tuomo Laitinen and Laitinen, {Jarmo T.} and Savinainen, {Juha R.}",
year = "2016",
month = oct,
day = "10",
doi = "10.1016/j.ejps.2016.08.031",
language = "English",
volume = "93",
pages = "253--263",
journal = "Norvegica Pharmaceutica Acta",
issn = "0928-0987",
publisher = "Elsevier",

}

RIS

TY - JOUR

T1 - Chemoproteomic, biochemical and pharmacological approaches in the discovery of inhibitors targeting human α/β-hydrolase domain containing 11 (ABHD11)

AU - Navia-Paldanius, Dina

AU - Patel, Jayendra Z.

AU - López Navarro, Miriam

AU - Jakupović, Hermina

AU - Goffart, Steffi

AU - Pasonen-Seppänen, Sanna

AU - Nevalainen, Tapio J.

AU - Jääskeläinen, Tiina

AU - Laitinen, Tuomo

AU - Laitinen, Jarmo T.

AU - Savinainen, Juha R.

PY - 2016/10/10

Y1 - 2016/10/10

N2 - ABHD11 (α/β-hydrolase domain containing 11) is a non-annotated enzyme belonging to the family of metabolic serine hydrolases (mSHs). Its natural substrates and products are unknown. Using competitive activity-based protein profiling (ABPP) to identify novel inhibitors of human (h)ABHD11, three compounds from our chemical library exhibited low nanomolar potency towards hABHD11. Competitive ABPP of various proteomes revealed fatty acid amide hydrolase (FAAH) as the sole off-target among the mSHs. Our fluorescent activity assays designed for natural lipase substrates revealed no activity of hABHD11 towards mono- or diacylglycerols. A broader profiling using para-nitrophenyl (pNP)-linked substrates indicated no amidase/protease, phosphatase, sulfatase, phospholipase C or phosphodiesterase activity. Instead, hABHD11 readily utilized para-nitrophenyl butyrate (pNPC4), indicating lipase/esterase-type activity that could be exploited in inhibitor discovery. Additionally, a homology model was created based on the crystal structure of bacterial esterase YbfF. In contrast to YbfF, which reportedly hydrolyze long-chain acyl-CoA, hABHD11 did not utilize oleoyl-CoA or arachidonoyl-CoA. In conclusion, the present study reports the discovery of potent hABHD11 inhibitors with good selectivity among mSHs. We developed substrate-based activity assays for hABHD11 that could be further exploited in inhibitor discovery and created the first homology-based hABHD11 model, offering initial insights into the active site of this poorly characterized enzyme.

AB - ABHD11 (α/β-hydrolase domain containing 11) is a non-annotated enzyme belonging to the family of metabolic serine hydrolases (mSHs). Its natural substrates and products are unknown. Using competitive activity-based protein profiling (ABPP) to identify novel inhibitors of human (h)ABHD11, three compounds from our chemical library exhibited low nanomolar potency towards hABHD11. Competitive ABPP of various proteomes revealed fatty acid amide hydrolase (FAAH) as the sole off-target among the mSHs. Our fluorescent activity assays designed for natural lipase substrates revealed no activity of hABHD11 towards mono- or diacylglycerols. A broader profiling using para-nitrophenyl (pNP)-linked substrates indicated no amidase/protease, phosphatase, sulfatase, phospholipase C or phosphodiesterase activity. Instead, hABHD11 readily utilized para-nitrophenyl butyrate (pNPC4), indicating lipase/esterase-type activity that could be exploited in inhibitor discovery. Additionally, a homology model was created based on the crystal structure of bacterial esterase YbfF. In contrast to YbfF, which reportedly hydrolyze long-chain acyl-CoA, hABHD11 did not utilize oleoyl-CoA or arachidonoyl-CoA. In conclusion, the present study reports the discovery of potent hABHD11 inhibitors with good selectivity among mSHs. We developed substrate-based activity assays for hABHD11 that could be further exploited in inhibitor discovery and created the first homology-based hABHD11 model, offering initial insights into the active site of this poorly characterized enzyme.

KW - ABHD11

KW - ABPP

KW - AFMID

KW - Homology modelling

KW - Inhibitor screening

KW - LYPLA2

KW - Serine hydrolases

UR - http://www.scopus.com/inward/record.url?scp=84984604676&partnerID=8YFLogxK

U2 - 10.1016/j.ejps.2016.08.031

DO - 10.1016/j.ejps.2016.08.031

M3 - Journal article

C2 - 27544863

AN - SCOPUS:84984604676

VL - 93

SP - 253

EP - 263

JO - Norvegica Pharmaceutica Acta

JF - Norvegica Pharmaceutica Acta

SN - 0928-0987

ER -

ID: 253189442