Targeting N-Terminal Human Maltase-Glucoamylase to Unravel Possible Inhibitors Using Molecular Docking, Molecular Dynamics Simulations, and Adaptive Steered Molecular Dynamics Simulations
There are multiple drugs for the treatment of type 2 diabetes, including traditional sulfonylureas biguanides, glinides, thiazolidinediones, α-glucosidase inhibitors, glucagon-like peptide-1 (GLP-1) receptor agonists, dipeptidyl peptidase IV (DPP-4) inhibitors, and sodium-glucose cotransporter 2 (SG...
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doaj-fb38f10f612d4c87a0063fb5bfebe1aa2021-09-03T14:44:44ZengFrontiers Media S.A.Frontiers in Chemistry2296-26462021-08-01910.3389/fchem.2021.711242711242Targeting N-Terminal Human Maltase-Glucoamylase to Unravel Possible Inhibitors Using Molecular Docking, Molecular Dynamics Simulations, and Adaptive Steered Molecular Dynamics SimulationsShitao Zhang0Yi Wang1Lu Han2Xueqi Fu3Song Wang4Wannan Li5Weiwei Han6School of Life Science, Key Laboratory for Molecular Enzymology and Engineering of Ministry of Education, National Engineering Laboratory for AIDS Vaccine, Jilin University, Changchun, ChinaSchool of Life Science, Key Laboratory for Molecular Enzymology and Engineering of Ministry of Education, National Engineering Laboratory for AIDS Vaccine, Jilin University, Changchun, ChinaSchool of Life Science, Key Laboratory for Molecular Enzymology and Engineering of Ministry of Education, National Engineering Laboratory for AIDS Vaccine, Jilin University, Changchun, ChinaSchool of Life Science, Key Laboratory for Molecular Enzymology and Engineering of Ministry of Education, National Engineering Laboratory for AIDS Vaccine, Jilin University, Changchun, ChinaLaboratory of Theoretical and Computational Chemistry, Institute of Theoretical Chemistry, Jilin University, Changchun, ChinaSchool of Life Science, Key Laboratory for Molecular Enzymology and Engineering of Ministry of Education, National Engineering Laboratory for AIDS Vaccine, Jilin University, Changchun, ChinaSchool of Life Science, Key Laboratory for Molecular Enzymology and Engineering of Ministry of Education, National Engineering Laboratory for AIDS Vaccine, Jilin University, Changchun, ChinaThere are multiple drugs for the treatment of type 2 diabetes, including traditional sulfonylureas biguanides, glinides, thiazolidinediones, α-glucosidase inhibitors, glucagon-like peptide-1 (GLP-1) receptor agonists, dipeptidyl peptidase IV (DPP-4) inhibitors, and sodium-glucose cotransporter 2 (SGLT2) inhibitors. α-Glucosidase inhibitors have been used to control postprandial glucose levels caused by type 2 diabetes since 1990. α-Glucosidases are rather crucial in the human metabolic system and are principally found in families 13 and 31. Maltase-glucoamylase (MGAM) belongs to glycoside hydrolase family 31. The main function of MGAM is to digest terminal starch products left after the enzymatic action of α-amylase; hence, MGAM becomes an efficient drug target for insulin resistance. In order to explore the conformational changes in the active pocket and unbinding pathway for NtMGAM, molecular dynamics (MD) simulations and adaptive steered molecular dynamics (ASMD) simulations were performed for two NtMGAM-inhibitor [de-O-sulfonated kotalanol (DSK) and acarbose] complexes. MD simulations indicated that DSK bound to NtMGAM may influence two domains (inserted loop 1 and inserted loop 2) by interfering with the spiralization of residue 497–499. The flexibility of inserted loop 1 and inserted loop 2 can influence the volume of the active pocket of NtMGAM, which can affect the binding progress for DSK to NtMGAM. ASMD simulations showed that compared to acarbose, DSK escaped from NtMGAM easily with lower energy. Asp542 is an important residue on the bottleneck of the active pocket of NtMGAM and could generate hydrogen bonds with DSK continuously. Our theoretical results may provide some useful clues for designing new α-glucosidase inhibitors to treat type 2 diabetes.https://www.frontiersin.org/articles/10.3389/fchem.2021.711242/fullmaltase-glucoamylaseinhibitorsmolecular dynamics simulationsadaptive steered molecular dynamics simulationsconformational change |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Shitao Zhang Yi Wang Lu Han Xueqi Fu Song Wang Wannan Li Weiwei Han |
spellingShingle |
Shitao Zhang Yi Wang Lu Han Xueqi Fu Song Wang Wannan Li Weiwei Han Targeting N-Terminal Human Maltase-Glucoamylase to Unravel Possible Inhibitors Using Molecular Docking, Molecular Dynamics Simulations, and Adaptive Steered Molecular Dynamics Simulations Frontiers in Chemistry maltase-glucoamylase inhibitors molecular dynamics simulations adaptive steered molecular dynamics simulations conformational change |
author_facet |
Shitao Zhang Yi Wang Lu Han Xueqi Fu Song Wang Wannan Li Weiwei Han |
author_sort |
Shitao Zhang |
title |
Targeting N-Terminal Human Maltase-Glucoamylase to Unravel Possible Inhibitors Using Molecular Docking, Molecular Dynamics Simulations, and Adaptive Steered Molecular Dynamics Simulations |
title_short |
Targeting N-Terminal Human Maltase-Glucoamylase to Unravel Possible Inhibitors Using Molecular Docking, Molecular Dynamics Simulations, and Adaptive Steered Molecular Dynamics Simulations |
title_full |
Targeting N-Terminal Human Maltase-Glucoamylase to Unravel Possible Inhibitors Using Molecular Docking, Molecular Dynamics Simulations, and Adaptive Steered Molecular Dynamics Simulations |
title_fullStr |
Targeting N-Terminal Human Maltase-Glucoamylase to Unravel Possible Inhibitors Using Molecular Docking, Molecular Dynamics Simulations, and Adaptive Steered Molecular Dynamics Simulations |
title_full_unstemmed |
Targeting N-Terminal Human Maltase-Glucoamylase to Unravel Possible Inhibitors Using Molecular Docking, Molecular Dynamics Simulations, and Adaptive Steered Molecular Dynamics Simulations |
title_sort |
targeting n-terminal human maltase-glucoamylase to unravel possible inhibitors using molecular docking, molecular dynamics simulations, and adaptive steered molecular dynamics simulations |
publisher |
Frontiers Media S.A. |
series |
Frontiers in Chemistry |
issn |
2296-2646 |
publishDate |
2021-08-01 |
description |
There are multiple drugs for the treatment of type 2 diabetes, including traditional sulfonylureas biguanides, glinides, thiazolidinediones, α-glucosidase inhibitors, glucagon-like peptide-1 (GLP-1) receptor agonists, dipeptidyl peptidase IV (DPP-4) inhibitors, and sodium-glucose cotransporter 2 (SGLT2) inhibitors. α-Glucosidase inhibitors have been used to control postprandial glucose levels caused by type 2 diabetes since 1990. α-Glucosidases are rather crucial in the human metabolic system and are principally found in families 13 and 31. Maltase-glucoamylase (MGAM) belongs to glycoside hydrolase family 31. The main function of MGAM is to digest terminal starch products left after the enzymatic action of α-amylase; hence, MGAM becomes an efficient drug target for insulin resistance. In order to explore the conformational changes in the active pocket and unbinding pathway for NtMGAM, molecular dynamics (MD) simulations and adaptive steered molecular dynamics (ASMD) simulations were performed for two NtMGAM-inhibitor [de-O-sulfonated kotalanol (DSK) and acarbose] complexes. MD simulations indicated that DSK bound to NtMGAM may influence two domains (inserted loop 1 and inserted loop 2) by interfering with the spiralization of residue 497–499. The flexibility of inserted loop 1 and inserted loop 2 can influence the volume of the active pocket of NtMGAM, which can affect the binding progress for DSK to NtMGAM. ASMD simulations showed that compared to acarbose, DSK escaped from NtMGAM easily with lower energy. Asp542 is an important residue on the bottleneck of the active pocket of NtMGAM and could generate hydrogen bonds with DSK continuously. Our theoretical results may provide some useful clues for designing new α-glucosidase inhibitors to treat type 2 diabetes. |
topic |
maltase-glucoamylase inhibitors molecular dynamics simulations adaptive steered molecular dynamics simulations conformational change |
url |
https://www.frontiersin.org/articles/10.3389/fchem.2021.711242/full |
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