Exploration of Cannabis constituents as potential candidates against diabetes mellitus disease using molecular docking, dynamics simulations and ADMET investigations

Abchir, Oussama; Daoui, Ossama; Nour, Hassan; Yamari, Imane; Elkhattabi, Souad; Errougui, Abdelkbir; Chtita, Samir

doi:10.1016/j.sciaf.2023.e01745

Cited by 14 publications

(6 citation statements)

References 45 publications

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“…To quantify the alignment, the RMSD was computed via the online tool DockRMSD ( ) (accessed 15 November 2023). [ 23 , 24 ], resulting in a value of 1.78 Å. This value underscores the remarkable consistency between the docked ligand and the co-crystalized ligand orientations.…”

Section: Resultsmentioning

confidence: 72%

“…Finally, we used the multiple linear regression (MLR) method to predict the biological activity of the data set as a linear function of the structural properties, which correlates the ordinate y (pIC 50 ) as a dependent variable to the molecular descriptors xi [ 17 , 18 , 19 , 20 , 21 , 22 , 23 , 24 , 25 , 26 , 27 , 28 , 29 , 30 , 31 , 32 , 33 , 34 , 35 , 36 , 37 , 38 , 39 , 40 , 41 ]. The analysis was conducted using SPSS version 19 for Windows [ 42 ].…”

Section: Methodsmentioning

confidence: 99%

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Computer-Aided Strategy on 5-(Substituted benzylidene) Thiazolidine-2,4-Diones to Develop New and Potent PTP1B Inhibitors: QSAR Modeling, Molecular Docking, Molecular Dynamics, PASS Predictions, and DFT Investigations

Derki,

Kerassa,

Belaidi

et al. 2024

Molecules

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A set of 5-(substituted benzylidene) thiazolidine-2,4-dione derivatives was explored to study the main structural requirement for the design of protein tyrosine phosphatase 1B (PTP1B) inhibitors. Utilizing multiple linear regression (MLR) analysis, we constructed a robust quantitative structure–activity relationship (QSAR) model to predict inhibitory activity, resulting in a noteworthy correlation coefficient (R2) of 0.942. Rigorous cross-validation using the leave-one-out (LOO) technique and statistical parameter calculations affirmed the model’s reliability, with the QSAR analysis revealing 10 distinct structural patterns influencing PTP1B inhibitory activity. Compound 7e(ref) emerged as the optimal scaffold for drug design. Seven new PTP1B inhibitors were designed based on the QSAR model, followed by molecular docking studies to predict interactions and identify structural features. Pharmacokinetics properties were assessed through drug-likeness and ADMET studies. After that density functional theory (DFT) was conducted to assess the stability and reactivity of potential diabetes mellitus drug candidates. The subsequent dynamic simulation phase provided additional insights into stability and interactions dynamics of the top-ranked compound 11c. This comprehensive approach enhances our understanding of potential drug candidates for treating diabetes mellitus.

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Section: Resultsmentioning

confidence: 72%

Section: Methodsmentioning

confidence: 99%

Computer-Aided Strategy on 5-(Substituted benzylidene) Thiazolidine-2,4-Diones to Develop New and Potent PTP1B Inhibitors: QSAR Modeling, Molecular Docking, Molecular Dynamics, PASS Predictions, and DFT Investigations

Derki,

Kerassa,

Belaidi

et al. 2024

Molecules

Self Cite

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“…Achieving more than two of these determinants can allow for the studied compound to have drug-like properties [48]. Other filters, such as Ghose, Veber, and Egan, for the studied polyflavonoids substantially help in identifying the bioavailability score [49], which was more significant in Lig II, Lig IV, and Lig V. Table 3 displays the pharmacokinetic parameters and drug-likeness properties elucidated for the studied compounds. Pharmacokinetic properties also deal with the availability of a predicted drug for partitioning in gastrointestinal cells with high proportions, such as Lig II, Lig IV, and Lig V, and low proportions such Lig I and Lig III, which resemble the control effect.…”

Section: Pharmacokinetic Parameters and Drug-likeness Predictionmentioning

confidence: 99%

The Synergistic Influence of Polyflavonoids from Citrus aurantifolia on Diabetes Treatment and Their Modulation of the PI3K/AKT/FOXO1 Signaling Pathways: Molecular Docking Analyses and In Vivo Investigations

Hassan,

Elmageed,

El-Qazaz

et al. 2023

Pharmaceutics

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This study was aimed at probing the modulatory influence of polyflavonoids extracted from Citrus aurantifolia, lemon peel extract (LPE-polyflavonoids), on attenuating diabetes mellitus (DM) and its complications. HPLC investigations of the LPE exhibited the incidence of five flavonoids, including diosmin, biochanin A, hesperidin, quercetin, and hesperetin. The in silico impact on ligand-phosphatidylinositol 3-kinase (PI3K) interaction was investigated in terms of polyflavonoid class to explore the non-covalent intakes and binding affinity to the known protein active site. The drug likeness properties and pharmacokinetic parameters of the LPE-polyflavonoids were investigated to assess their bioavailability in relation to Myricetin as a control. Remarkably, the molecular docking studies demonstrated a prominent affinity score of all these agents together with PI3K, implying the potency of the extract to orchestrate PI3K, which is the predominant signal for lessening the level of blood glucose. To verify these findings, in vivo studies were conducted, utilizing diabetic male albino rats treated with LPE-polyflavonoids and other groups treated with hesperidin and diosmin as single flavonoids. Our findings demonstrated that the LPE-polyflavonoids significantly ameliorated the levels of glucose, insulin, glycogen, liver function, carbohydrate metabolizing enzymes, G6Pd, and AGEs compared to the diabetic rats and those exposed to hesperidin and diosmin. Furthermore, the LPE-polyflavonoids regulated the TBARS, GSH, CAT, TNF-α, IL-1β, IL-6, and AFP levels in the pancreatic and hepatic tissues, suggesting their antioxidant and anti-inflammatory properties. In addition, the pancreatic and hepatic GLUT4 and GLUT2 were noticeably increased in addition to the pancreatic p-AKT in the rats administered with the LPE-polyflavonoids compared to the other diabetic rats. Remarkably, the administration of LPE-polyflavonoids upregulated the expression of the pancreatic and hepatic PI3K, AMPK, and FOXO1 genes, emphasizing the efficiency of the LPE in orchestrating all the signaling pathways necessitated to reduce the diabetes mellitus. Notably, the histopathological examinations of the pancreatic and hepatic tissues corroborated the biochemical results. Altogether, our findings accentuated the potential therapeutic role of LPE-polyflavonoids in controlling diabetes mellitus.

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“…Diabetes mellitus (DM) is a chronic metabolic disorder characterized by hyperglycemia, which can be caused by reduced insulin action, inadequate insulin synthesis, or both [ 1 ]. Hyperglycemia typically aggravates the disease burden of diabetes mellitus by contributing to the development of different macrovascular complications like peripheral and autonomic neuropathy, an increased incidence of atherosclerosis, cerebrovascular diseases, neuropathy, nephropathy, and retinopathy [ 2 ].…”

Section: Introductionmentioning

confidence: 99%

“…The onset of diabetes mellitus is linked to diverse lifestyle factors, including smoking, excessive alcohol consumption, inadequate physical activity, and comorbid conditions such as dyslipidemia and hypertension. Additionally, genetic predisposition, stress, and obesity contribute to the risk of diabetes [ 5 ], while enzymes like alpha-glucosidase and amylase play a role in breaking down sugars into glucose and maltose, contributing to the increase in blood glucose levels, ultimately resulting in hyperglycemia and posing challenges to the proper functioning of insulin [ 2 ].…”

Section: Introductionmentioning

confidence: 99%

Integrative Approach for Designing Novel Triazole Derivatives as α-Glucosidase Inhibitors: QSAR, Molecular Docking, ADMET, and Molecular Dynamics Investigations

Abchir,

Khedraoui,

Nour

et al. 2024

Pharmaceuticals

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In response to the increasing prevalence of diabetes mellitus and the limitations associated with the current treatments, there is a growing need to develop novel medications for this disease. This study is focused on creating new compounds that exhibit a strong inhibition of alpha-glucosidase, which is a pivotal enzyme in diabetes control. A set of 33 triazole derivatives underwent an extensive QSAR analysis, aiming to identify the key factors influencing their inhibitory activity against α-glucosidase. Using the multiple linear regression (MLR) model, seven promising compounds were designed as potential drugs. Molecular docking and dynamics simulations were employed to shed light on the mode of interaction between the ligands and the target, and the stability of the obtained complexes. Furthermore, the pharmacokinetic properties of the designed compounds were assessed to predict their behavior in the human body. The binding free energy was also calculated using MMGBSA method and revealed favorable thermodynamic properties. The results highlighted three novel compounds with high biological activity, strong binding affinity to the target enzyme, and suitability for oral administration. These results offer interesting prospects for the development of effective and well-tolerated medications against diabetes mellitus.

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Exploration of Cannabis constituents as potential candidates against diabetes mellitus disease using molecular docking, dynamics simulations and ADMET investigations

Cited by 14 publications

References 45 publications

Computer-Aided Strategy on 5-(Substituted benzylidene) Thiazolidine-2,4-Diones to Develop New and Potent PTP1B Inhibitors: QSAR Modeling, Molecular Docking, Molecular Dynamics, PASS Predictions, and DFT Investigations

Computer-Aided Strategy on 5-(Substituted benzylidene) Thiazolidine-2,4-Diones to Develop New and Potent PTP1B Inhibitors: QSAR Modeling, Molecular Docking, Molecular Dynamics, PASS Predictions, and DFT Investigations

The Synergistic Influence of Polyflavonoids from Citrus aurantifolia on Diabetes Treatment and Their Modulation of the PI3K/AKT/FOXO1 Signaling Pathways: Molecular Docking Analyses and In Vivo Investigations

Integrative Approach for Designing Novel Triazole Derivatives as α-Glucosidase Inhibitors: QSAR, Molecular Docking, ADMET, and Molecular Dynamics Investigations

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