Targeting N-Terminal Human Maltase-Glucoamylase to Unravel Possible Inhibitors Using Molecular Docking, Molecular Dynamics Simulations, and Adaptive Steered Molecular Dynamics Simulations

Abstract

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.

Phenolics from Chrozophora oblongifolia Aerial Parts as Inhibitors of α-Glucosidases and Advanced Glycation End Products: In-Vitro Assessment, Molecular Docking and Dynamics Studies

“…Applying the cut-off mobility threshold at ∆RMSF of 0.3 Å, higher flexibility/mobility patterns were assigned for the N-terminal residues as compared to those of the carboxy end (Figure 9). This was consistent with the MD dynamic behavior of the hMGAM proteins reported by Zhang and his research group [59] as well as the reported conformational stability and B-factor analyses regarding the hMGAM crystalline structures [51,[53][54][55][56]. The latter would highlight the validity of the presented MD simulation study and adopted protocol.…”

“…Steady complex Cα-RMSDs tones were depicted for both ligands around averages of 2.7 ± 0.2 Å and 2.9 ± 0.2 Å for the investigated gallotannin derivative and acarbose, respectively. Comparable acarbose-based dynamic findings were also reported by Zhang et al for unraveling possible inhibitors of the hMGAM biological target [59]. Concerning the sole ligand's Cα-RMSDs, higher average values were assigned for the docked gallotannin compound in relation to the co-crystalline acarbose (5.2 ± 0.5 Å versus 2.9 ± 0.6 Å) till the half of the MD simulation run.…”

Characterization of the SGLT2 Interaction Network and Its Regulation by SGLT2 Inhibitors: A Bioinformatic Analysis

“…MGAM main function is to digest terminal starch products left after the enzymatic action of α-amylase; hence, MGAM becomes a promising drug target for treating insulin resistance ( Pałasz et al, 2019 ; Zhang et al, 2021 ). In our study, it appeared in six of the seven shortest paths analyses.…”

Deciphering Molecular Aspects of Potential α-Glucosidase Inhibitors within Aspergillus terreus: A Computational Odyssey of Molecular Docking-Coupled Dynamics Simulations and Pharmacokinetic Profiling

“…Setting the binding site for docking was guided by the information obtained from the co-crystallized ligand bounded to the hi MGAG target protein. A grid docking box was created to accommodate all essential amino acids being viewed at the deposited complex file, as well as those being reported as crucial for the anchoring of small molecule ligands [ 28 , 34 , 35 , 36 ]. Using the grid generation tool within AutoDock, a grid box was constructed at the center atom of the co-crystallized ligand, with an external size of 80 Å × 80 Å × 80 Å and 0.38 Å grid-point spacing along the XYZ-cartesian coordinates.…”