Rational Design of Novel Inhibitors of α-Glucosidase: An Application of Quantitative Structure Activity Relationship and Structure-Based Virtual Screening
Abstract:α-Glucosidase is considered a prime drug target for Diabetes Mellitus and its inhibitors are used to delay carbohydrate digestion for the treatment of diabetes mellitus. With the aim to design α-glucosidase inhibitors with novel chemical scaffolds, three folds ligand and structure based virtual screening was applied. Initially linear quantitative structure activity relationship (QSAR) model was developed by a molecular operating environment (MOE) using a training set of thirty-two known inhibitors, which showe… Show more
“…It should be noted, most α-glucosidase inhibitors which are available today as diabetes medicine, can also inhibit α-amylase, and therefore specific α-glucosidase inhibitors are probably more tolerable 8 . On the other hand, the potent and safe α-glucosidase inhibitors can be useful in the treatment of obesity and other α-glucosidase related diseases 9 – 11 . Figure 1 Schematic diagram illustrating the mechanism of action of α-amylase and α-glucosidase (ChemDraw 18.2).…”
In the present work, a new series of 14 novel phthalimide-benzenesulfonamide derivatives 4a–n were synthesized, and their inhibitory activity against yeast α-glucosidase was screened. The obtained results indicated that most of the newly synthesized compounds showed prominent inhibitory activity against α-glucosidase. Among them, 4-phenylpiperazin derivative 4m exhibited the strongest inhibition with the IC50 value of 52.2 ± 0.1 µM. Enzyme kinetic study of compound 4m proved that its inhibition mode was competitive and Ki value of this compound was calculated to be 52.7 µM. In silico induced fit docking and molecular dynamics studies were performed to further investigate the interaction, orientation, and conformation of the target compounds over the active site of α-glucosidase. Obtained date of these studies demonstrated that our new compounds interacted as well with the α-glucosidase active site with the acceptable binding energies. Furthermore, in silico druglikeness/ADME/Toxicity studies of compound 4m were performed and predicted that this compound is druglikeness and has good ADME and toxicity profiles.
“…It should be noted, most α-glucosidase inhibitors which are available today as diabetes medicine, can also inhibit α-amylase, and therefore specific α-glucosidase inhibitors are probably more tolerable 8 . On the other hand, the potent and safe α-glucosidase inhibitors can be useful in the treatment of obesity and other α-glucosidase related diseases 9 – 11 . Figure 1 Schematic diagram illustrating the mechanism of action of α-amylase and α-glucosidase (ChemDraw 18.2).…”
In the present work, a new series of 14 novel phthalimide-benzenesulfonamide derivatives 4a–n were synthesized, and their inhibitory activity against yeast α-glucosidase was screened. The obtained results indicated that most of the newly synthesized compounds showed prominent inhibitory activity against α-glucosidase. Among them, 4-phenylpiperazin derivative 4m exhibited the strongest inhibition with the IC50 value of 52.2 ± 0.1 µM. Enzyme kinetic study of compound 4m proved that its inhibition mode was competitive and Ki value of this compound was calculated to be 52.7 µM. In silico induced fit docking and molecular dynamics studies were performed to further investigate the interaction, orientation, and conformation of the target compounds over the active site of α-glucosidase. Obtained date of these studies demonstrated that our new compounds interacted as well with the α-glucosidase active site with the acceptable binding energies. Furthermore, in silico druglikeness/ADME/Toxicity studies of compound 4m were performed and predicted that this compound is druglikeness and has good ADME and toxicity profiles.
“…from a virtual screening study; however these molecules have not been tested for α-amylase activity. Halim et al 18 have reported a virtual screening study using a subset of ZINC database coupled with QSAR study as an rational approach to identify α-glucosidase inhibitors; the molecules have been screening against S. cerevisiae α-glucosidase.…”
Diabetes is a major health issue that half a billion people affected worldwide. It is a serious, long-term medical condition majorly impacting the lives and well-being of individuals, families, and societies at large. It is amongst the top 10 diseases responsible for the death amongst adults with an expected rise to 10.2% (578 million) by 2030 and 10.9% (700 million) by 2045. The carbohydrates absorbed into the body are hydrolyzed by pancreatic α-amylase and other enzymes, human α-glucosidase. The α-amylase and α-glucosidase are validated therapeutic targets in the treatment of Type II diabetes (T2DM) as they play a vital role in modulating the blood glucose post meal. Herein, we report novel and diverse molecules as potential candidates, with predicted affinity for α-amylase and α-glucosidase. These molecules have been identified via hierarchical multistep docking of small molecules database with the estimated binding free energies. A Glide XP Score cutoff −8.00 kcal/mol was implemented to filter out non potential molecules. Four molecules viz. amb22034702, amb18105639, amb17153304, and amb9760832 have been identified after an exhaustive computational study involving, evaluation of binding interactions and assessment of the pharmacokinetics and toxicity profiles. The in-depth analysis of protein– ligand interactions was performed using a 100ns molecular dynamics (MD) simulation to establish the dynamic stability. Furthermore MM-GBSA based binding free energies were computed for 1000 trajectory snapshots to ascertain the strong binding affinity of these molecules for α-amylase and αglucosidase. The identified molecules can be considered as promising candidates for further drug development through necessary experimental assessments.
“…The substrate molecule (isomaltose) cocrystallized in the isomaltase 3D structure was manually docked in the a-glucosidase by aligning the protein sequence and structure, and the RMSD of the protein structure and sequence alignment was reported. 23 To validate the docking protocols, the redocking was performed using the substrate molecule with the α-glucosidase active site residues. The superimposed RMSD of the reported substrate and the redocked substrate was calculated in angstrom (Å).…”
A novel series of multifunctional benzimidazoles has been reported as potent inhibitors of α-glucosidase. The procedure relies on the synthesis of 5-amino-1H-benzo[d]imidazole-2-thiol 5 via the multistep reaction through 2-nitroaniline 1, benzene-1,2-diamine 2, 1H-benzo[d]imidazole-2-thiol 3, and 5-nitro-1H-benzo[d]imidazole-2-thiol 4. Further treatment of 5 with aromatic aldehydes 6a−m provided access to the target 5-(arylideneamino)-1H-benzo[d]imidazole-2-thiols 7a−m.The results of the bioactivity assessment revealed all the compounds as excellent inhibitors of the enzyme (IC 50 range: 0.64 ± 0.05 μM to 343.10 ± 1.62 μM) than acarbose (873.34 ± 1.21). Among them, 7i was the most active inhibitor (IC 50 : 0.64 ± 0.05 μM) followed by 7d
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