Unveiling potent Schiff base derivatives with selective xanthine oxidase inhibition: In silico and in vitro approach.

This research describes the synthesis by an environmentally-friendly method, microwave irradiation, development and analysis of three novel and one previously identified Schiff base derivative as a potential inhibitor of bovine xanthine oxidase (BXO), a key enzyme implicated in the progression of gout. Meticulous experimentation revealed that these compounds (10, 9, 4, and 7) have noteworthy inhibitory effects on BXO, with IC50 values ranging from 149.56 µM to 263.60 µM, indicating their good efficacy compared to that of the standard control. The validation of these results was further enhanced through comprehensive in silico studies, which revealed the pivotal interactions between the inhibitors and the catalytic sites of BXO, with a particular emphasis on the imine group (-C = N-) functionalities. Intriguingly, the compounds exhibiting the highest inhibition rates also showcase advantageous ADMET profiles, alongside encouraging initial assessments via PASS, hinting at their broad-spectrum potential. The implications of these findings are profound, suggesting that these Schiff base derivatives not only offer a new vantage point for the inhibition of BXO but also hold considerable promise as innovative therapeutic agents in the management and treatment of gout, marking a significant leap forward in the quest for more effective gout interventions.

Exploring the Anti-Cancer Potential of Hispidin: A Comprehensive in Silico and in Vitro Study on Human Osteosarcoma Saos2 Cells.

Hispidin was initially discovered in basidiomycete Inonotus hispidus (Bull.) P. Karst and this extraordinary compound possesses immense potency and can be extracted from the wild mushroom through specialized bioreactor cultivation techniques. In our study, we isolated it from Inonotus hispidus (Bull.) P. Karst., with a yield of 3.6 %. We identified and characterized hispidin through the implementation of spectroscopic techniques such as FTIR, NMR, and MS. Additionally, we utilized Thermogravimetric Analysis for thermal characterization of the compound. Computational studies based on DFT were performed to investigate the molecular structure, electronic properties, and chemical reactivity of hispidin. PASS analysis for hispidin demonstrated that 19 of them are anti-neoplastic activities. The Pharmacology prediction of hispidin confirm that it is not toxic, non-carcinogenesis with a good human intestinal absorption. The effect of hispidin on the viability of bone cancer cells was evaluated by MTT assay. The results showed that hispidin significantly reduced SaoS2 cell viability in a dose-dependent manner. Molecular docking was carried out using five targets related to bone cancer to determine the interactions between hispidin and the studied proteins. The results demonstrate that hispidin is a good inhibitor for the five targets. Dynamic simulation shows a good stability of the complex hispidin-protein.

HPLC-DAD-MS Characterization, Antioxidant Activity, α-amylase Inhibition, Molecular Docking, and ADMET of Flavonoids from Fenugreek Seeds.

Fenugreek (Trigonella foenum-graecum) has a great beneficial health effect; it has been used in traditional medicine by many cultures. Likewise, the α-amylase inhibitors are potential compounds in the development of drugs for the treatment of diabetes. The beneficial health effects of fenugreek lead us to explore the chemical composition of the seeds and their antioxidant and α-amylase inhibition activities. The flavonoid extraction from fenugreek seeds was achieved with methanol through a Soxhlet apparatus. Then, the flavonoid glycosides were characterized using HPLC-DAD-ESI-MS analysis. The antioxidant capacity of fenugreek seed was measured using DPPH, FRAP, ABTS, and CUPRAC assays. Finally, the α-amylase inhibition activity was carried out using in vitro and in silico methods. The methanolic extract was found to contain high amounts of total phenolics (154.68 ± 1.50 µg GAE/mg E), flavonoids (37.69 ± 0.73 µg QE/mg E). The highest radical-scavenging ability was recorded for the methanolic extract against DPPH (IC50 = 556.6 ± 9.87 µg/mL), ABTS (IC50 = 593.62 ± 9.35 µg/mL). The ME had the best reducing power according to the CUPRAC (A 0.5 = 451.90 ± 9.07 µg/mL). The results indicate that the methanolic extracts of fenugreek seed best α-amylase inhibition activities IC50 = 653.52 ± 3.24 µg/mL. Twenty-seven flavonoids were detected, and all studied flavonoids selected have good affinity and stabilize very well in the pocket of α-amylase. The interactions between the studied flavonoids with α-amylase were investigated. The flavonoids from fenugreek seed present a good inhibitory effect against α-amylase, which is beneficial for the prevention of diabetes and its complications.

In silico analysis of identified molecules using LC-HR/MS of Cupressus sempervirens L. ethyl acetate fraction against three monkeypox virus targets.

Monkeypox virus is a viral disease transmitted to humans through contact with infected animals, such as monkeys and rodents, or through direct contact with the bodily fluids or lesions of infected humans. The aim of this study is to evaluate in silico the inhibition effect of eight Cupressus sempervirens L. ethyl acetate fraction identified molecules using LC-MS on three monkeypox targets such as the vaccinia virus thymidylate kinase (VTK), the viral profilin-like protein (VPP), and the viral RNA polymerase (VRP). The study consist of using molecular docking with AutoDock vina based on the lowest energy value in kcal/mol, pharmacokinetics prediction with pre-ADMET v2.0 server, and prediction of biological activity with the PASS server tool. The best complexes were subjected to molecular dynamics simulation (MD) study to confirm their stability using Desmond software. The used molecules were vitamin C, vanillic acid (Pol), Flav1 (Catechin), Flav2 (Epicatechin), Flav3 (Hyperoside), Flav4 (Luteolin), Flav5 (Taxifolin), and Flav6 (Quercetin). The results show that flavonoids are potent to VTK, VPP and effectively block the VRP channel with energy values ranging from -7.0 to -9.3 kcal/mol. Further, MD simulation supports Flav1 and, Flav2 for notable stability in the VTK binding pocket through hydrogen and hydrophobic interactions. PASS results predicted various biological activities with promising VTK and VRP inhibition activities. The studied molecules could constitute a safer alternative to current drugs, which often cause adverse side effects.Communicated by Ramaswamy H. Sarma.

Hydroxycoumarins and some Flavonoids from Pistacia atlantica Desf. as Multi-targets Inhibitors for Alzheimer's Disease: Molecular Docking and ADMET Studies.

OBJECTIVE: The present study aimed to identify new selective inhibitors for acetylcholinesterase, butyrylcholinesterase, monoacylglycerol lipase, beta-secretase, and Asparagine endopeptidase, the targets enzymes in Alzheimer's disease. METHODS: The inhibitory effect of P. atlantica Desf. methanol extracts against AChE were determined using Ellman's method. The molecular docking study is achieved using Autodock Vina. The structures of the molecules 3-methoxycarpachromene, masticadienonic acid, 7-ethoxycoumarin, 3',5,7- trihydroxy-4'-methoxyflavanone and 5,6,7,4'-tetrahydroxyflavonol-3-O-rutinoside and the five enzymes were obtained from the PubChem database and Protein databank. ADMET parameters were checked to confirm their pharmacokinetics using swiss-ADME and ADMET-SAR servers. RESULTS: P. atlantica Desf. methanol extracts showed a notable inhibitory effect against AChE (IC50 = 0.26 ± 0.004 mg/ml). The molecular docking results of 3-methoxycarpachromene, masticadienonic acid, 7-ethoxycoumarin, 3',5,7-trihydroxy-4'-methoxyflavanone and 5,6,7,4'-tetrahydroxyflavonol-3-Orutinoside with the five enzymes show significant affinities of these molecules towards Alzheimer disease targets, where they could form several interactions, such as hydrogen bonds and hydrophobic interactions with the studied enzymes. The shortest hydrogen bond is 1.7 A° between masticadienonic acid and Arg128 of the active site of BACE, while the lowest free energy is -11.2 of the complex 5,6,7,4'-tetrahydroxyflavonol-3-O-rutinoside -HuBchE. To the best of our knowledge, these molecules' potential anti-Alzheimer disease effect is studied in this paper for the first time. CONCLUSION: The docking studies of this work show that 3-methoxycarpachromene and masticadienonic acid, 7-ethoxycoumarin, 3',5,7-Trihydroxy-4'-methoxyflavanone and 5,6,7,4'-tetrahydroxyflavonol- 3-O-rutinoside have good affinities towards the enzymes involved in Alzheimer pathology, which confirm the ability of these molecules to inhibit the studied enzymes namely: HuAChE, HuBChE, BACE, MAGL, and AEP. These molecules might become drug candidates to prevent Alzheimer's disease.

Repurposing antibiotics as potent multi-drug candidates for SARS-CoV-2 delta and omicron variants: molecular docking and dynamics.

There is a daunting public health emergency due to the emergence and rapid global spread of the new omicron variants of SARS-CoV-2. The variants differ in many characteristics, such as transmissibility, antigenicity and the immune system of the human hosts' shifting responses. This change in characteristics raises concern, as it leads to unknown consequences and also raises doubts about the efficacy of the currently available vaccines. As of March 2022, there are five variants of SARS-CoV-2 disseminating: the alpha, the beta, the gamma, the delta and the omicron variant. The omicron variant has more than 30 mutations on the spike protein, which is used by the virus to enter the host cell and is also used as a target for the vaccines. In this work, we studied the possible anti-COVID-19 effect of two molecules by molecular docking using Autodock Vina and molecular dynamic simulations using Gromacs 2020 software. We docked amoxicillin and clavulanate to the main protease (Mpro), the RNA-dependent RNA polymerase (RdRp) and the spike protein receptor-binding domain (SRBD) of the wild type with the two variants (delta and omicron) of SARS-CoV-2. The docking results show that the ligands bound tightly with the SRBD of the omicron variant, while the dynamic simulation revealed the ability of amoxicillin to bind to the SRBD of both variants' delta and omicron. The high number of mutations that occurred in both variants increases the affinity of amoxicillin towards them.Communicated by Ramaswamy H. Sarma.

Cupressus sempervirens L. flavonoids as potent inhibitors to xanthine oxidase: in vitro, molecular docking, ADMET and PASS studies.

Excessive intake of purine-rich foods such as seafood and red meat leads to excess xanthine oxidase activity and provokes gout attacks. The aim of this paper is to evaluate in vitro and in silico, the inhibition effect of Cupressus sempervirens plant extracts (flavonoids (Cae) and alkaloids (CaK)) and its six derivative compounds on bovine xanthine oxidase (BXO). The in silico study consists of molecular docking with GOLD v4.0 based on the best PLPchem score (PLP) and prediction of biological activity with the PASS server tool. The inhibitors used were lignan (cp1), Amentoflavone (cp2), Cupressuflavone (cp3), Isocryptomerin (cp4), Hinokiflavone (cp5), and Neolignan (cp6). The in vitro results showed that CaK gives an IC50 of 3.52 ± 0.04 µg/ml. Similarly, Cae saved an IC50 of 8.46 ± 1.98 µg/ml compared with the control (2.82 ± 0.10 µg/ml). The in silico results show that cp1 was the best inhibitor model (PLP of 88.09) with approved pharmacokinetics. These findings suggest that cp1 and cp2 may offer good alternatives for the treatment of hyperuricemia; cp3 was moderate, while the others (cp4 to cp6) were considered weak inhibitors according to their PLP.Communicated by Ramaswamy H. Sarma.

Hispidin and Lepidine E: Two Natural Compounds and Folic Acid as Potential Inhibitors of 2019-novel Coronavirus Main Protease (2019- nCoVMpro), Molecular Docking and SAR Study.

BACKGROUND: 2019-nCoVis, a novel coronavirus was isolated and identified in 2019 in the city of Wuhan, China. On February 17, 2020 and according to the World Health Organization, 71, 429 confirmed cases worldwide were identified, among them 2162 new cases were recorded in the last 24 hours. One month later, the confirmed cases jumped to 179111, with 11525 new cases in the last 24 hours, with 7426 total deaths. No drug or vaccine is present at the moment for human and animal coronavirus. METHODS: The inhibition of 3CL hydrolase enzyme provides a promising therapeutic principle for developing treatments against CoViD-19. The 3CLpro (Mpro) is known for involving in counteracting the host innate immune response. RESULTS: This work presents the inhibitory effect of some natural compounds against 3CL hydrolase enzyme, and explains the main interactions in inhibitor-enzyme complex. Molecular docking study was carried out using Autodock Vina. By screening several molecules, we identified three candidate agents that inhibit the main protease of coronavirus. Hispidin, lepidine E, and folic acid are bound tightly in the enzyme, therefore strong hydrogen bonds have been formed (1.69-1.80Å) with the active site residues. CONCLUSION: This study provides a possible therapeutic strategy for CoViD-19.

Seeds, Leaves and Roots of Thapsia garganica as a Source of New Potent Lipases Inhibitors: In vitro and In silico Studies.

BACKGROUND AND OBJECTIVE: Lipase inhibitors have gained great interest because they could help in the therapy of many diseases, however, unfortunately, only a few drugs are currently available on the market. Therefore, the aim of this work was to evaluate for the first time the lipase inhibition effect of Thapsia garganica extracts from seeds, leaves and roots. METHODS: Polyphenols and flavonoids contents were determined using spectrophotometric method. Inhibitory activity of ethyl acetate extracts from seeds, leaves and roots of T. garganica against Candida rugosa lipase was determined. To uncover the active constituents responsible for this anti-lipase activity, further investigations were performed by employing theoretical docking simulations, using AutoDock Vina program to discuss the nature of interactions and the inhibition mechanism by major bioactive compounds synthesized by this plant. RESULTS: Seeds, leaves and roots extracts of T. garganica showed appreciable contents of polyphenols and flavonoids which is most in seeds extract with 2.90±0.02mg GAE/gdw and 1.53±0.05mg QE/gdw, respectively. Hence, their inhibitory activities against Candida rugosa lipase were determined as IC50 of 1.19mg/ml, 1.96mg/ml and 1.87mg/ml, respectively. Docking simulations have shown that nortribolid and tribolid are best inhibitors for both lipases (Candida rugosa and human pancreatic lipases). CONCLUSION: Testing the anti-lipase activity of the ethyl acetate extracts of T. garganica revealed a potent lipase inhibition activity, which suggests the use of these molecules as anti-obesity drugs.

The Inhibitory Effect of Some Drugs on Candida rugosa Lipase and Human Pancreatic Lipase: In vitro and In silico Studies.

BACKGROUND AND OBJECTIVE: Side effects of some drugs may be useful in certain cases. In this work, we studied the inhibitory effects on Lipases of some medications as: Folic Acid which is taken by pregnant women, Colchicine and Febuxostat which is used as treatment of gout disease. These cases are linked to obesity, where women (BMI ≥ 30) have twice higher odds of having an NTDaffected pregnancy than the normal weight women, and the Gout disease frequently occurs in combination of a Metabolic syndrome. The risk of gout increases with the increase of the mass index. In silico studies were aimed to determine the mechanism of inhibition and different interactions for two enzymes: Candida rugosa lipase and human pancreatic lipase. METHODS: In the first part of this study, we studied the inhibition activity of these medications on lipase activity of Candida rugosa in vitro. Autodock vina was used for molecular docking with 50 runs and 1000 obtained solutions. The saved interactions were with His449 and Ser209 for the three molecules. RESULTS: The results show that these drugs have an important inhibition activity with IC50 values 0.64 mg/ml for Folic acid and 0.66 mg/ml for Febuxostat. The results of in silico show competitive, Noncompetitive and uncompetitive inhibition for folic acid, febuxostat and colchicine respectively for two enzymes with different repetition ratios of hydrogen bonds. CONCLUSION: These observations support a higher intake of dietary folate, and febuxostat for losing weight to decrease NTD risk and prevent hyperuricemia and recurrent gout attacks.