Recent Trends in Enzyme Inhibition and Activation in Drug Design

Geronikaki, Athina

doi:10.3390/molecules26010017

Cited by 18 publications

(11 citation statements)

References 21 publications

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“…Enzymes intervene in metabolic reactions in the body, and imbalances in enzyme activity cause illnesses that can be corrected by blocking the enzyme activity [ 56 , 57 ]. Enzyme inhibition is, therefore, the basis of many drugs.…”

Section: Discussionmentioning

confidence: 99%

In Vitro and In Silico Evaluation of Anticholinesterase and Antidiabetic Effects of Furanolabdanes and Other Constituents from Graptophyllum pictum (Linn.) Griffith

Metiefeng,

Tamfu,

Fotsing Tagatsing

et al. 2023

Molecules

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Graptophyllum pictum is a tropical plant noticeable for its variegated leaves and exploited for various medicinal purposes. In this study, seven compounds, including three furanolabdane diterpenoids, i.e., Hypopurin E, Hypopurin A and Hypopurin B, as well as with Lupeol, β-sitosterol 3-O-β-d-glucopyranoside, stigmasterol 3-O-β-d-glucopyranoside and a mixture of β-sitosterol and stigmasterol, were isolated from G. pictum, and their structures were deduced from ESI-TOF-MS, HR-ESI-TOF-MS, 1D and 2D NMR experiments. The compounds were evaluated for their anticholinesterase activities against acetylcholinesterase (AChE) and butyrylcholinesterase (BchE), as well as their antidiabetic potential through inhibition of α-glucosidase and α-amylase. For AChE inhibition, no sample had IC50 within tested concentrations, though the most potent was Hypopurin A, which had a percentage inhibition of 40.18 ± 0.75%, compared to 85.91 ± 0.58% for galantamine, at 100 µg/mL. BChE was more susceptible to the leaves extract (IC50 = 58.21 ± 0.65 µg/mL), stem extract (IC50 = 67.05 ± 0.82 µg/mL), Hypopurin A (IC50 = 58.00 ± 0.90 µg/mL), Hypopurin B (IC50 = 67.05 ± 0.92 µg/mL) and Hypopurin E (IC50 = 86.90 ± 0.76 µg/mL). In the antidiabetic assay, the furanolabdane diterpenoids, lupeol and the extracts had moderate to good activities. Against α-glucosidase, lupeol, Hypopurin E, Hypopurin A and Hypopurin B had appreciable activities but the leaves (IC50 = 48.90 ± 0.17 µg/mL) and stem (IC50 = 45.61 ± 0.56 µg/mL) extracts were more active than the pure compounds. In the α-amylase assay, stem extract (IC50 = 64.47 ± 0.78 µg/mL), Hypopurin A (IC50 = 60.68 ± 0.55 µg/mL) and Hypopurin B (IC50 = 69.51 ± 1.30 µg/mL) had moderate activities compared to the standard acarbose (IC50 = 32.25 ± 0.36 µg/mL). Molecular docking was performed to determine the binding modes and free binding energies of Hypopurin E, Hypopurin A and Hypopurin B in relation to the enzymes and decipher the structure–activity relationship. The results indicated that G. pictum and its compounds could, in general, be used in the development of therapies for Alzheimer’s disease and diabetes.

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Section: Discussionmentioning

confidence: 99%

In Vitro and In Silico Evaluation of Anticholinesterase and Antidiabetic Effects of Furanolabdanes and Other Constituents from Graptophyllum pictum (Linn.) Griffith

Metiefeng,

Tamfu,

Fotsing Tagatsing

et al. 2023

Molecules

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“…The samples were analyzed in triplicate to ensure the reproducibility of the results. The total flavonoid content (TFC) was determined by the aluminum chloride method with slight modification [ 13 , 75 ], where 300 μL of AlCl 3 (1:10 w / v ) was added to 0.5 mL of each sample, mixed, and left to react at room temperature for 10 min, to measure after that their absorbance at 510 nm. Catechin concentrations ranging from 0 to 1200 μg/mL were prepared, and a standard calibration curve was obtained using a linear fit.…”

Section: Methodsmentioning

confidence: 99%

“…Enzymes are involved in most biochemical processes in the living system, and an imbalance of enzyme activity can lead to pathological conditions such as inflammation, microbial infections, diabetes, HIV, Alzheimer’s disease (AD), and hyperpigmentation [ 11 , 12 , 13 ]. Correcting metabolic imbalances can be provided by blocking enzyme activity using inhibitors which can be reversible or irreversible.…”

Section: Introductionmentioning

confidence: 99%

Assessment of Chemical Composition and In Vitro Antioxidant, Antidiabetic, Anticholinesterase and Microbial Virulence-Quenching Effects of Salad Burnet (Sanguisorba minor L.) Harvested from Algeria

Haouam,

Boudiba,

Tamfu

et al. 2023

Plants

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Sanguisorba minor is a medicinal vegetable used in seasoning desserts, juices, and beverages. An evaluation of the total flavonoid, phenolic, tannin and anthocyanin contents indicated that these classes of compounds are distributed variably in the different fractions. In summary, the HPLC-DAD analyses enabled the identification and quantification of thirteen phenolic compounds in an ethyl acetate extract (EAE), nine in a dichloromethane extract (DCME), seven in an aqueous extract (AQE) and four in a butanol extract (BE). Rutin was the most abundant phenolic compound in the BE (278.4 ± 1.20 µg/g) and AQE (32.87 ± 0.23 µg/g) fractions, while apigenin was the most abundant in the DCME (84.75 ± 0.60 µg/g) and EAE (156.8 ± 0.95 µg/g) fractions. The presence of phenolic compounds in the fractions conferred good antioxidant capacity, especially the EAE and DCME fractions, which both exhibited higher antioxidant effects than BHA and α-tocopherol in DPPH• and CUPRAC assays. Additionally, in the ABTS•+ assay, EAE (IC50 = 9.27 ± 0.33 µg/mL) was more active than α-tocopherol (IC50 = 35.50 ± 0.55 µg/mL), and BHA (IC50 = 12.70 ± 0.10 µg/mL). At 200 µg/mL, the fractions inhibited acetylcholinesterase and butyrylcholinesterase as well as α-amylase and α-glucosidase, indicating that they can slow neurodegeneration and hyperglycemia. Minimal inhibitory concentration (MIC) values ranged from 0.312 mg/mL to 1.25 mg/mL, and fractions showed good biofilm inhibition against Staphylococcus aureus and Escherichia coli. The extracts exhibited good violacein inhibition in Chromobacterium violaceum CV12472 and Chromobacterium violaceum CV026, despite the supply of external acyl-homoserine lactone to CV026. The antioxidant, quorum-sensing, antibiofilm and enzyme inhibition attributes indicate the potential for the application of S. minor as a food preservative.

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“…To date, the disease is without a cure, with only available therapies, including insulin shots and oral hypoglycemic agents, being designated for overcoming stages of broad glycemia [ 2 ]. Within the modern research of drug discovery, targeting enzymes related to specific disorders for inhibition has been considered a relevant approach [ 5 ].…”

Section: Introductionmentioning

confidence: 99%

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

Elhady,

Alshobaki,

Elfaky

et al. 2023

Metabolites

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Hyperglycemia, as a hallmark of the metabolic malady diabetes mellitus, has been an overwhelming healthcare burden owing to its high rates of comorbidity and mortality, as well as prospective complications affecting different body organs. Available therapeutic agents, with α-glucosidase inhibitors as one of their cornerstone arsenal, control stages of broad glycemia while showing definitive characteristics related to their low clinical efficiency and off-target complications. This has propelled the academia and industrial section into discovering novel and safer candidates. Herein, we provided a thorough computational exploration of identifying candidates from the marine-derived Aspergillus terreus isolates. Combined structural- and ligand-based approaches using a chemical library of 275 metabolites were adopted for pinpointing promising α-glucosidase inhibitors, as well as providing guiding insights for further lead optimization and development. Structure-based virtual screening through escalating precision molecular docking protocol at the α-glucosidase canonical pocket identified 11 promising top-docked hits, with several being superior to the market drug reference, acarbose. Comprehensive ligand-based investigations of these hits’ pharmacokinetics ADME profiles, physiochemical characterizations, and obedience to the gold standard Lipinski’s rule of five, as well as toxicity and mutagenicity profiling, proceeded. Under explicit conditions, a molecular dynamics simulation identified the top-stable metabolites: butyrolactone VI (SK-44), aspulvinone E (SK-55), butyrolactone I 4′’’’-sulfate (SK-72), and terrelumamide B (SK-173). They depicted the highest free binding energies and steadiest thermodynamic behavior. Moreover, great structural insights have been revealed, including the advent of an aromatic scaffold-based interaction for ligand–target complex stability. The significance of introducing balanced hydrophobic/polar moieties, like triazole and other bioisosteres of carboxylic acid, has been highlighted across docking, ADME/Tox profiling, and molecular dynamics studies for maximizing binding interactions while assuring safety and optimal pharmacokinetics for targeting the intestinal-localized α-glucosidase enzyme. Overall, this study provided valuable starting points for developing new α-glucosidase inhibitors based on nature-derived unique scaffolds, as well as guidance for prospective lead optimization and development within future pre-clinical and clinical investigations.

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Recent Trends in Enzyme Inhibition and Activation in Drug Design

Abstract: It is known that enzymes are involved in many pathological conditions, such as inflammation, diabetes, microbial infections, HIV, neoplastic, neglected diseases and others [...]

Cited by 18 publications

References 21 publications

In Vitro and In Silico Evaluation of Anticholinesterase and Antidiabetic Effects of Furanolabdanes and Other Constituents from Graptophyllum pictum (Linn.) Griffith

In Vitro and In Silico Evaluation of Anticholinesterase and Antidiabetic Effects of Furanolabdanes and Other Constituents from Graptophyllum pictum (Linn.) Griffith

Assessment of Chemical Composition and In Vitro Antioxidant, Antidiabetic, Anticholinesterase and Microbial Virulence-Quenching Effects of Salad Burnet (Sanguisorba minor L.) Harvested from Algeria

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

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