Discovery of triterpenoids as reversible inhibitors of a/ß- hydrolase domain containing 12 (ABHD12)

T Parkkari, R Haavikko, T Laitinen, D Navia-Paldanius, R Rytilahti, M Vaara, M Lehtonen, Sami Alakurtti, J Yli-Kauhaluoma, T Nevalainen, J R Savinainen, J T Laitinen (Corresponding Author)

    Research output: Contribution to journalArticleScientificpeer-review

    19 Citations (Scopus)

    Abstract

    Background: a/ß-hydrolase domain containing (ABHD)12 is a recently discovered serine hydrolase that acts in vivo as a lysophospholipase for lysophosphatidylserine. Dysfunctional ABHD12 has been linked to the rare neurodegenerative disorder called PHARC (polyneuropathy, hearing loss, ataxia, retinosis pigmentosa, cataract). In vitro, ABHD12 has been implicated in the metabolism of the endocannabinoid 2-arachidonoylglycerol (2-AG). Further studies on ABHD12 function are hampered as no selective inhibitor have been identified to date. In contrast to the situation with the other endocannabinoid hydrolases, ABHD12 has remained a challenging target for inhibitor development as no crystal structures are available to facilitate drug design. Methodology/ Principal Findings: Here we report the unexpected discovery that certain triterpene-based structures inhibit human ABHD12 hydrolase activity in a reversible manner, the best compounds showing submicromolar potency. Based on structure activity relationship (SAR) data collected for 68 natural and synthetic triterpenoid structures, a pharmacophore model has been constructed. A pentacyclic triterpene backbone with carboxyl group at position 17, small hydrophobic substituent at the position 4, hydrogen bond donor or acceptor at position 3 accompanied with four axial methyl substituents was found crucial for ABHD12 inhibitor activity. Although the triterpenoids typically may have multiple protein targets, we witnessed unprecedented selectivity for ABHD12 among the metabolic serine hydrolases, as activity-based protein profiling of mouse brain membrane proteome indicated that the representative ABHD12 inhibitors did not inhibit other serine hydrolases, nor did they target cannabinoid receptors. Conclusions/Significance: We have identified reversibly-acting triterpene-based inhibitors that show remarkable selectivity for ABHD12 over other metabolic serine hydrolases. Based on SAR data, we have constructed the first pharmacophore model of ABHD12 inhibitors. This model should pave the way for further discovery of novel lead structures for ABHD12 selective inhibitors
    Original languageEnglish
    Article numbere98286
    JournalPLoS ONE
    Volume9
    Issue number5
    DOIs
    Publication statusPublished - 2014
    MoE publication typeA1 Journal article-refereed

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    Hydrolases
    hydrolases
    triterpenoids
    serine
    Serine
    Endocannabinoids
    Triterpenes
    structure-activity relationships
    Structure-Activity Relationship
    Pentacyclic Triterpenes
    lysophospholipase
    Lysophospholipase
    Cannabinoid Receptors
    Polyneuropathies
    cataract
    Drug Design
    neurodegenerative diseases
    Audition
    hearing
    Ataxia

    Cite this

    Parkkari, T., Haavikko, R., Laitinen, T., Navia-Paldanius, D., Rytilahti, R., Vaara, M., ... Laitinen, J. T. (2014). Discovery of triterpenoids as reversible inhibitors of a/ß- hydrolase domain containing 12 (ABHD12). PLoS ONE, 9(5), [e98286]. https://doi.org/10.1371/journal.pone.0098286
    Parkkari, T ; Haavikko, R ; Laitinen, T ; Navia-Paldanius, D ; Rytilahti, R ; Vaara, M ; Lehtonen, M ; Alakurtti, Sami ; Yli-Kauhaluoma, J ; Nevalainen, T ; Savinainen, J R ; Laitinen, J T. / Discovery of triterpenoids as reversible inhibitors of a/ß- hydrolase domain containing 12 (ABHD12). In: PLoS ONE. 2014 ; Vol. 9, No. 5.
    @article{be8a647e910146ac800b40dd4338ab68,
    title = "Discovery of triterpenoids as reversible inhibitors of a/{\ss}- hydrolase domain containing 12 (ABHD12)",
    abstract = "Background: a/{\ss}-hydrolase domain containing (ABHD)12 is a recently discovered serine hydrolase that acts in vivo as a lysophospholipase for lysophosphatidylserine. Dysfunctional ABHD12 has been linked to the rare neurodegenerative disorder called PHARC (polyneuropathy, hearing loss, ataxia, retinosis pigmentosa, cataract). In vitro, ABHD12 has been implicated in the metabolism of the endocannabinoid 2-arachidonoylglycerol (2-AG). Further studies on ABHD12 function are hampered as no selective inhibitor have been identified to date. In contrast to the situation with the other endocannabinoid hydrolases, ABHD12 has remained a challenging target for inhibitor development as no crystal structures are available to facilitate drug design. Methodology/ Principal Findings: Here we report the unexpected discovery that certain triterpene-based structures inhibit human ABHD12 hydrolase activity in a reversible manner, the best compounds showing submicromolar potency. Based on structure activity relationship (SAR) data collected for 68 natural and synthetic triterpenoid structures, a pharmacophore model has been constructed. A pentacyclic triterpene backbone with carboxyl group at position 17, small hydrophobic substituent at the position 4, hydrogen bond donor or acceptor at position 3 accompanied with four axial methyl substituents was found crucial for ABHD12 inhibitor activity. Although the triterpenoids typically may have multiple protein targets, we witnessed unprecedented selectivity for ABHD12 among the metabolic serine hydrolases, as activity-based protein profiling of mouse brain membrane proteome indicated that the representative ABHD12 inhibitors did not inhibit other serine hydrolases, nor did they target cannabinoid receptors. Conclusions/Significance: We have identified reversibly-acting triterpene-based inhibitors that show remarkable selectivity for ABHD12 over other metabolic serine hydrolases. Based on SAR data, we have constructed the first pharmacophore model of ABHD12 inhibitors. This model should pave the way for further discovery of novel lead structures for ABHD12 selective inhibitors",
    author = "T Parkkari and R Haavikko and T Laitinen and D Navia-Paldanius and R Rytilahti and M Vaara and M Lehtonen and Sami Alakurtti and J Yli-Kauhaluoma and T Nevalainen and Savinainen, {J R} and Laitinen, {J T}",
    year = "2014",
    doi = "10.1371/journal.pone.0098286",
    language = "English",
    volume = "9",
    journal = "PLoS ONE",
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    Parkkari, T, Haavikko, R, Laitinen, T, Navia-Paldanius, D, Rytilahti, R, Vaara, M, Lehtonen, M, Alakurtti, S, Yli-Kauhaluoma, J, Nevalainen, T, Savinainen, JR & Laitinen, JT 2014, 'Discovery of triterpenoids as reversible inhibitors of a/ß- hydrolase domain containing 12 (ABHD12)', PLoS ONE, vol. 9, no. 5, e98286. https://doi.org/10.1371/journal.pone.0098286

    Discovery of triterpenoids as reversible inhibitors of a/ß- hydrolase domain containing 12 (ABHD12). / Parkkari, T; Haavikko, R; Laitinen, T; Navia-Paldanius, D; Rytilahti, R; Vaara, M; Lehtonen, M; Alakurtti, Sami; Yli-Kauhaluoma, J; Nevalainen, T; Savinainen, J R; Laitinen, J T (Corresponding Author).

    In: PLoS ONE, Vol. 9, No. 5, e98286, 2014.

    Research output: Contribution to journalArticleScientificpeer-review

    TY - JOUR

    T1 - Discovery of triterpenoids as reversible inhibitors of a/ß- hydrolase domain containing 12 (ABHD12)

    AU - Parkkari, T

    AU - Haavikko, R

    AU - Laitinen, T

    AU - Navia-Paldanius, D

    AU - Rytilahti, R

    AU - Vaara, M

    AU - Lehtonen, M

    AU - Alakurtti, Sami

    AU - Yli-Kauhaluoma, J

    AU - Nevalainen, T

    AU - Savinainen, J R

    AU - Laitinen, J T

    PY - 2014

    Y1 - 2014

    N2 - Background: a/ß-hydrolase domain containing (ABHD)12 is a recently discovered serine hydrolase that acts in vivo as a lysophospholipase for lysophosphatidylserine. Dysfunctional ABHD12 has been linked to the rare neurodegenerative disorder called PHARC (polyneuropathy, hearing loss, ataxia, retinosis pigmentosa, cataract). In vitro, ABHD12 has been implicated in the metabolism of the endocannabinoid 2-arachidonoylglycerol (2-AG). Further studies on ABHD12 function are hampered as no selective inhibitor have been identified to date. In contrast to the situation with the other endocannabinoid hydrolases, ABHD12 has remained a challenging target for inhibitor development as no crystal structures are available to facilitate drug design. Methodology/ Principal Findings: Here we report the unexpected discovery that certain triterpene-based structures inhibit human ABHD12 hydrolase activity in a reversible manner, the best compounds showing submicromolar potency. Based on structure activity relationship (SAR) data collected for 68 natural and synthetic triterpenoid structures, a pharmacophore model has been constructed. A pentacyclic triterpene backbone with carboxyl group at position 17, small hydrophobic substituent at the position 4, hydrogen bond donor or acceptor at position 3 accompanied with four axial methyl substituents was found crucial for ABHD12 inhibitor activity. Although the triterpenoids typically may have multiple protein targets, we witnessed unprecedented selectivity for ABHD12 among the metabolic serine hydrolases, as activity-based protein profiling of mouse brain membrane proteome indicated that the representative ABHD12 inhibitors did not inhibit other serine hydrolases, nor did they target cannabinoid receptors. Conclusions/Significance: We have identified reversibly-acting triterpene-based inhibitors that show remarkable selectivity for ABHD12 over other metabolic serine hydrolases. Based on SAR data, we have constructed the first pharmacophore model of ABHD12 inhibitors. This model should pave the way for further discovery of novel lead structures for ABHD12 selective inhibitors

    AB - Background: a/ß-hydrolase domain containing (ABHD)12 is a recently discovered serine hydrolase that acts in vivo as a lysophospholipase for lysophosphatidylserine. Dysfunctional ABHD12 has been linked to the rare neurodegenerative disorder called PHARC (polyneuropathy, hearing loss, ataxia, retinosis pigmentosa, cataract). In vitro, ABHD12 has been implicated in the metabolism of the endocannabinoid 2-arachidonoylglycerol (2-AG). Further studies on ABHD12 function are hampered as no selective inhibitor have been identified to date. In contrast to the situation with the other endocannabinoid hydrolases, ABHD12 has remained a challenging target for inhibitor development as no crystal structures are available to facilitate drug design. Methodology/ Principal Findings: Here we report the unexpected discovery that certain triterpene-based structures inhibit human ABHD12 hydrolase activity in a reversible manner, the best compounds showing submicromolar potency. Based on structure activity relationship (SAR) data collected for 68 natural and synthetic triterpenoid structures, a pharmacophore model has been constructed. A pentacyclic triterpene backbone with carboxyl group at position 17, small hydrophobic substituent at the position 4, hydrogen bond donor or acceptor at position 3 accompanied with four axial methyl substituents was found crucial for ABHD12 inhibitor activity. Although the triterpenoids typically may have multiple protein targets, we witnessed unprecedented selectivity for ABHD12 among the metabolic serine hydrolases, as activity-based protein profiling of mouse brain membrane proteome indicated that the representative ABHD12 inhibitors did not inhibit other serine hydrolases, nor did they target cannabinoid receptors. Conclusions/Significance: We have identified reversibly-acting triterpene-based inhibitors that show remarkable selectivity for ABHD12 over other metabolic serine hydrolases. Based on SAR data, we have constructed the first pharmacophore model of ABHD12 inhibitors. This model should pave the way for further discovery of novel lead structures for ABHD12 selective inhibitors

    U2 - 10.1371/journal.pone.0098286

    DO - 10.1371/journal.pone.0098286

    M3 - Article

    VL - 9

    JO - PLoS ONE

    JF - PLoS ONE

    SN - 1932-6203

    IS - 5

    M1 - e98286

    ER -

    Parkkari T, Haavikko R, Laitinen T, Navia-Paldanius D, Rytilahti R, Vaara M et al. Discovery of triterpenoids as reversible inhibitors of a/ß- hydrolase domain containing 12 (ABHD12). PLoS ONE. 2014;9(5). e98286. https://doi.org/10.1371/journal.pone.0098286