Integrating virtual screening, pharmacoinformatics profiling, and molecular dynamics: identification of promising inhibitors targeting 3CLpro of SARS-CoV-2.

Introduction: The pursuit of effective therapeutic solutions for SARS-CoV-2 infections and COVID-19 necessitates the repurposing of existing compounds. This study focuses on the detailed examination of the central protease, 3-chymotrypsin-like protease (3CLpro), a pivotal player in virus replication. The combined approach of molecular dynamics simulations and virtual screening is employed to identify potential inhibitors targeting 3CLpro. Methods: A comprehensive virtual screening of 7120 compounds sourced from diverse databases was conducted. Four promising inhibitors, namely EN1036, F6548-4084, F6548-1613, and PUBT44123754, were identified. These compounds exhibited notable attributes, including high binding affinity (ranging from -5.003 to -5.772 Kcal/mol) and superior Induced Fit Docking scores (ranging from -671.66 to -675.26 Kcal/mol) compared to co-crystallized ligands. Results: In-depth analysis revealed that F6548-1613 stood out, demonstrating stable hydrogen bonds with amino acids His41 and Thr62. Notably, F6548-1613 recorded a binding energy of -65.72 kcal/mol in Molecular Mechanics Generalized Born Surface Area (MMGBSA) simulations. These findings were supported by Molecular Dynamics simulations, highlighting the compound's efficacy in inhibiting 3CLpro. Discussion: The identified compounds, in compliance with Lipinski's rule of five and exhibiting functional molecular interactions with 3CLpro, present promising therapeutic prospects. The integration of in silico methodologies significantly expedites drug discovery, laying the foundation for subsequent experimental validation and optimization. This approach holds the potential to develop effective therapeutics for SARS-CoV-2.

GC-MS Profiling, In Vitro Antioxidant, Antimicrobial, and In Silico NADPH Oxidase Inhibition Studies of Essential Oil of Juniperus thurifera Bark.

Juniperus thurifera is a native species to the mountains of the western Mediterranean region. It is used in traditional medicine as a natural treatment against infections. The present study aimed to carry out the chemical analysis and evaluate the antioxidant, antimicrobial, as well as in silico inhibition studies of the essential oils from Juniperus thurifera bark (EOEJT). Chemical characterization of EOEJT was done by gas chromatography (GC-MS). We have performed three antioxidant assays (Reducing power (FRAP), 2, 2-diphenylpicrylhydrazyl (DPPH), and total antioxidant capacity (TAC)) of the EOEJT. We next evaluated the antimicrobial activity against in silico study, which was carried out to help evaluate the inhibitory effect of EOEJT against NADPH oxidase. Results of the GC/MS analysis revealed seven major compounds in EOEJT wherein muurolol (36%) and elemol (26%) were the major components. Moreover, EOEJT possessed interesting antioxidant potential with an IC50 respectively of 21.25 ± 1.02 µg/mL, 481.02 ± 5.25 µg/mL, and 271 µg EAA/mg in DPPH, FRAP, and total antioxidant capacity systems. Molecular docking of EOEJT in NADPH oxidase active site showed inhibitory activity of α-cadinol and muurolol with a glide score of -6.041 and -5.956 Kcal/mol, respectively. As regards the antibacterial and antifungal capacities, EOEJT was active against all tested bacteria and all fungi, notably, against Escherichia coli K12 with an inhibition diameter of 21 mm and a MIC value of 0.67 mg/mL, as well as against Proteus mirabilis ATCC 29906 with an inhibition diameter of 18.33 ± 1.15 mm and a MIC value of 1.34 mg/mL. A more pronounced effect was recorded for the fungal pathogens Fusarium oxysporum MTCC 9913 with inhibition of 37.44 ± 0.28% and MIC value of 6.45 mg/mL, as well as against Candida albicans ATCC 10231 with an inhibition diameter of 20.33 ± 1.15 mm and a MIC value of 0.67 ± 0.00 mg/mL. Altogether, these results highlight the importance of EOEJT as a source of natural antibacterial and antioxidant drugs to fight clinically important pathogenic strains.

Effect of C. cyminum and L. sativum on Pharmacokinetics and Pharmacodynamics of Antidiabetic Drug Gliclazide.

BACKGROUND: Numerous herbs are reported to have anti-hyperglycemic activity and are frequently used in combination with prescription drugs to lower the blood glucose levels in diabetic patients, without proper knowledge about the possibility of herb-drug interaction. OBJECTIVES: To investigate the effect of cumin and garden cress on pharmacokinetics (PK) and pharmacodynamics (PD) of gliclazide (GLZ) in nicotinamide-streptozotocin diabetic model. METHODS: Diabetic animals of groups II-IV were treated with GLZ, cumin, 'cumin + GLZ', garden cress and 'garden cress + GLZ'. Herb's treatments were given for two weeks, and GLZ was administered in a single dose. Blood glucose levels (BGLs) were measured at pre-determined time points. Plasma samples of pharmacokinetic study were analyzed using UPLC-MS/MS. GLZ fragment at m/z 324.1>127 was monitored. RESULTS: Cumin and garden cress have shown 15.3% and 15.9% reduction in mean BGL (1-24h) (p-value < 0.001), respectively. GLZ reduced mean BGL by 30.0%, which was significantly better than cumin and garden cress (pvalue <0.05). Concurrently administered "garden cress + GLZ" demonstrated the highest reduction in mean BGL (by 40.46%) and showed a prolonged effect. There was no significant advantage of simultaneously administered 'cumin + GLZ'. Cumin did not affect PK of GLZ. Garden cress has significantly enhanced AUC0-t (by 69.8%, pvalue 0.0013), but other PK parameters Cmax, Tmax, and Kel were close to the control group. CONCLUSION: PK/PD-based herb-drug interaction was observed. Concurrently administered garden cress + GLZ showed improved antidiabetic effect and has enhanced GLZ bioavailability.