Reynolds C

References (2)

Title : Probing the Interactions of Thiazole Abietane Inhibitors with the Human Serine Hydrolases ABHD16A and ABHD12 - Ahonen_2023_ACS.Med.Chem.Lett_14_1404
Author(s) : Ahonen TJ , Ng CP , Farinha B , Almeida B , Victor BL , Reynolds C , Kalso E , Yli-Kauhaluoma J , Greaves J , Moreira VM
Ref : ACS Med Chem Lett , 14 :1404 , 2023
Abstract : 12-Thiazole abietanes are highly selective reversible inhibitors of hABHD16A that could potentially alleviate neuroinflammation. In this study, we used synthetic chemistry, competitive activity-based protein profiling, and computational methodologies to try to establish relevant structural determinants of activity and selectivity of this class of compounds for inhibiting ABHD16A over ABHD12. Five compounds significantly inhibited hABHD16A but also very efficiently discriminated between inhibition of hABHD16A and hABHD12, with compound 35 being the most effective, at 100 microM (55.1 +/- 8.7%; p < 0.0001). However, an outstanding switch in the selectivity toward ABHD12 was observed in the presence of a ring A ester, if the C2' position of the thiazole ring possessed a 1-hydroxyethyl group, as in compound 28. Although our data were inconclusive as to whether the observed enzyme inhibition is allosteric or not, we anticipate that the structure-activity relationships presented herein will inspire future drug discovery efforts in this field.
ESTHER : Ahonen_2023_ACS.Med.Chem.Lett_14_1404
PubMedSearch : Ahonen_2023_ACS.Med.Chem.Lett_14_1404
PubMedID: 37849541
Gene_locus related to this paper: human-ABHD12 , human-ABHD16A

Title : Crystal structure of a soluble form of human monoglyceride lipase in complex with an inhibitor at 1.35 A resolution - Schalk-Hihi_2011_Protein.Sci_20_670
Author(s) : Schalk-Hihi C , Schubert C , Alexander R , Bayoumy S , Clemente JC , Deckman I , Desjarlais RL , Dzordzorme KC , Flores CM , Grasberger B , Kranz JK , Lewandowski F , Liu L , Ma H , Maguire D , Macielag MJ , McDonnell ME , Mezzasalma Haarlander T , Miller R , Milligan C , Reynolds C , Kuo LC
Ref : Protein Science , 20 :670 , 2011
Abstract : A high-resolution structure of a ligand-bound, soluble form of human monoglyceride lipase (MGL) is presented. The structure highlights a novel conformation of the regulatory lid-domain present in the lipase family as well as the binding mode of a pharmaceutically relevant reversible inhibitor. Analysis of the structure lacking the inhibitor indicates that the closed conformation can accommodate the native substrate 2-arachidonoyl glycerol. A model is proposed in which MGL undergoes conformational and electrostatic changes during the catalytic cycle ultimately resulting in its dissociation from the membrane upon completion of the cycle. In addition, the study outlines a successful approach to transform membrane associated proteins, which tend to aggregate upon purification, into a monomeric and soluble form.
ESTHER : Schalk-Hihi_2011_Protein.Sci_20_670
PubMedSearch : Schalk-Hihi_2011_Protein.Sci_20_670
PubMedID: 21308848
Gene_locus related to this paper: human-MGLL