دورية أكاديمية
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Kinetics and molecular modeling studies on the inhibition mechanism of GH13 α-glycosidases by small molecule ligands.

التفاصيل البيبلوغرافية
العنوان: Kinetics and molecular modeling studies on the inhibition mechanism of GH13 α-glycosidases by small molecule ligands.
المؤلفون: Senger MR; Laboratório de Bioquímica Experimental e Computacional de Fármacos, Instituto Oswaldo Cruz, Fundação Oswaldo Cruz, Rio de Janeiro, Brazil., da Costa Latgé SG; Laboratório de Bioquímica e Fisiologia de Insetos, Instituto Oswaldo Cruz, Fundação Oswaldo Cruz, Rio de Janeiro, Brazil., von Ranke NL; Laboratório de Bioquímica Experimental e Computacional de Fármacos, Instituto Oswaldo Cruz, Fundação Oswaldo Cruz, Rio de Janeiro, Brazil., de Aquino GAS; Laboratório de Síntese Orgânica e Prospecção Biológica, Instituto de Química, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil., Dantas RF; Laboratório de Bioquímica Experimental e Computacional de Fármacos, Instituto Oswaldo Cruz, Fundação Oswaldo Cruz, Rio de Janeiro, Brazil., Genta FA; Laboratório de Bioquímica e Fisiologia de Insetos, Instituto Oswaldo Cruz, Fundação Oswaldo Cruz, Rio de Janeiro, Brazil., Ferreira SB; Laboratório de Síntese Orgânica e Prospecção Biológica, Instituto de Química, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil., Junior FPS; Laboratório de Bioquímica Experimental e Computacional de Fármacos, Instituto Oswaldo Cruz, Fundação Oswaldo Cruz, Rio de Janeiro, Brazil. Electronic address: floriano@ioc.fiocruz.br.
المصدر: International journal of biological macromolecules [Int J Biol Macromol] 2024 Jun; Vol. 269 (Pt 1), pp. 132036. Date of Electronic Publication: 2024 May 01.
نوع المنشور: Journal Article
اللغة: English
بيانات الدورية: Publisher: Elsevier Country of Publication: Netherlands NLM ID: 7909578 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1879-0003 (Electronic) Linking ISSN: 01418130 NLM ISO Abbreviation: Int J Biol Macromol Subsets: MEDLINE
أسماء مطبوعة: Publication: Amsterdam : Elsevier
Original Publication: Guildford, Eng., IPC Science and Technology Press.
مواضيع طبية MeSH: Molecular Docking Simulation* , Molecular Dynamics Simulation*, Kinetics ; Ligands ; Swine ; Glycoside Hydrolase Inhibitors/pharmacology ; Glycoside Hydrolase Inhibitors/chemistry ; Animals ; Catalytic Domain ; alpha-Glucosidases/metabolism ; alpha-Glucosidases/chemistry ; Glycoside Hydrolases/chemistry ; Glycoside Hydrolases/metabolism ; Glycoside Hydrolases/antagonists & inhibitors ; Small Molecule Libraries/pharmacology ; Small Molecule Libraries/chemistry ; Triazoles/chemistry ; Triazoles/pharmacology ; Models, Molecular
مستخلص: Alpha-glucosidase inhibitors play an important role in Diabetes Mellitus (DM) treatment since they prevent postprandial hyperglycemia. The Glycoside Hydrolase family 13 (GH13) is the major family of enzymes acting on substrates containing α-glucoside linkages, such as maltose and amylose/amylopectin chains in starch. Previously, our group identified glycoconjugate 1H-1,2,3-triazoles (GCTs) inhibiting two GH13 α-glycosidases: yeast maltase (MAL12) and porcine pancreatic amylase (PPA). Here, we combined kinetic studies and computational methods on nine GCTs to characterize their inhibitory mechanism. They all behaved as reversible inhibitors, and kinetic models encompassed noncompetitive and various mechanisms of mixed-type inhibition for both enzymes. Most potent inhibitors displayed K i values of 30 μM for MAL12 (GPESB16) and 37 μM for PPA (GPESB15). Molecular dynamics and docking simulations indicated that on MAL12, GPESB15 and GPESB16 bind in a cavity adjacent to the active site, while on the PPA, GPESB15 was predicted to bind at the entrance of the catalytic site. Notably, despite its putative location within the active site, the binding of GPESB15 does not obstruct the substrate's access to the cleavage site. Our study contributes to paving the way for developing novel therapeutic strategies for managing DM-2 through GH13 α-glycosidases inhibition.
Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
(Copyright © 2024 Elsevier B.V. All rights reserved.)
فهرسة مساهمة: Keywords: Anti-hyperglycemic triazoles; GH13 glycosidases; Kinetic inhibition mechanism
المشرفين على المادة: 0 (Ligands)
0 (Glycoside Hydrolase Inhibitors)
EC 3.2.1.20 (alpha-Glucosidases)
EC 3.2.1.- (Glycoside Hydrolases)
0 (Small Molecule Libraries)
0 (Triazoles)
تواريخ الأحداث: Date Created: 20240502 Date Completed: 20240529 Latest Revision: 20240529
رمز التحديث: 20240529
DOI: 10.1016/j.ijbiomac.2024.132036
PMID: 38697429
قاعدة البيانات: MEDLINE
الوصف
تدمد:1879-0003
DOI:10.1016/j.ijbiomac.2024.132036