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.

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.

Anti-inflammatory drugs as new inhibitors to xanthine oxidase: In vitro and in silico approach.

The two important targets to treat gout disease are (1) control the hyperuricemia by the inhibition of Xanthine Oxidase (XO) and (2) treatment of acute attacks of gout by the use of anti-inflammatory drugs. It is important to distinguish between therapy to manage hyperuricemia and to reduce acute inflammation. While reducing hyperuricemia is resolved very slowly with available drugs, gout symptoms like pain and inflammation may become persistent. The objective of this study is to find a relevant treatment with a beneficial double effect. (1) As an anti-inflammatory, analgesic, and antipyretic effect and (2) as XO inhibitory effect, which is the main objective of this study. We investigated the effect of five non-steroidal anti-inflammatory drugs (NSAIDs) against human and bovine milk xanthine oxidases (HXO and BXO) using the double enzyme detection method (DED) and molecular docking with the Autodock vina program. in vitro results show that the NSAIDs give an important inhibition to HXO and BXO with an IC50 of 2.04 ± 0.13 µg/ml, 2.75 ± 0.23 µg/ml, 1.45 ± 0.19 µg/ml, 0.31 ± 0.13 µg/ml and 1.27 ± 0.11 µg/ml, for HXO, and 2.96 ± 0.27 µg/ml, 9.46 ± 0.13 µg/ml, 6.21 ± 1.17 µg/ml, 0.83 ± 0.11 µg/ml, and 3.48 ± 0.13 µg/ml, for BXO, for respectively, Naproxen, Ibuprofen, Diclofenac, Indomethacin, and Celecoxib. Testing the inhibitory activity of these drugs on both XOs shows an important inhibition, especially from Indomethacin, which could be a promising lead compound for reducing acute inflammation and at the same time controlling hyperuricemia.

Hispidin, Harmaline, and Harmine as potent inhibitors of bovine xanthine oxidase: Gout treatment, in vitro, ADMET prediction, and SAR studies.

Alkaloids and phenols are potent inhibitors family for many enzymes used in many therapies. We aim to evaluate in vitro and in silico, the inhibition effect of Hispidin, Harmaline, and Harmine as pure molecules to bovine milk xanthine oxidase (BXO), Molecular docking and SAR study with GOLD was done to explain the mechanism of action related to its inhibition, ADMET parameters were checked to confirm their pharmacokinetics (PK) using preADMET 2.0 server, we classified our inhibitors by applying five drug-likeness rules, the best-ranked inhibitors were chosen based on the approved ADMET properties, drug-likeness qualifications, and the best PLPchem score generated by GOLD. The in vitro results show important inhibition activity to BXO comparing to the control with an IC50 of 39.72 ± 3.60 µM, 51.00 ± 1.0 µM, and 48.52 ± 1.76 µM for Hispidin, Harmaline, and Harmine respectively. The in silico results show that Hispidin was the best inhibitor model with approved ADMET properties and qualification in all drug-likeness rules; Harmaline was saved second-best model to BXO with suitable ADMET properties and qualified in most drug-likeness rules. Eventually, Harmine was ranked third potent inhibitor model with acceptable ADMET properties, drug-likeness rules, and PLPchem score. The tested inhibitors could be significant in drug discovery, especially in treating gout disease; therefore, drug development, including clinical trials, should be done with promising results.

Synthesis, Structure and Impact of 5-Aminoorotic Acid and Its Complexes with Lanthanum(III) and Gallium(III) on the Activity of Xanthine Oxidase.

The superoxide radical ion is involved in numerous physiological processes, associated with both health and pathology. Its participation in cancer onset and progression is well documented. Lanthanum(III) and gallium(III) are cations that are known to possess anticancer properties. Their coordination complexes are being investigated by the scientific community in the search for novel oncological disease remedies. Their complexes with 5-aminoorotic acid suppress superoxide, derived enzymatically from xanthine/xanthine oxidase (X/XO). It seems that they, to differing extents, impact the enzyme, or the substrate, or both. The present study closely examines their chemical structure by way of modern methods-IR, Raman, and 1H NMR spectroscopy. Their superoxide-scavenging behavior in the presence of a non-enzymatic source (potassium superoxide) is compared to that in the presence of an enzymatic source (X/XO). Enzymatic activity of XO, defined in terms of the production of uric acid, seems to be impacted by both complexes and the pure ligand in a concentration-dependent manner. In order to better relate the compounds' chemical characteristics to XO inhibition, they were docked in silico to XO. A molecular docking assay provided further proof that 5-aminoorotic acid and its complexes with lanthanum(III) and gallium(III) very probably suppress superoxide production via XO inhibition.

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.

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.

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.

The inhibitory kinetics of vitamins B9, C, E, and D3 on bovine xanthine oxidase: Gout treatment.

BACKGROUND: Over-consumption of foods high in purines like seafood, red meat, and alcoholic beverages leads to hyperuricemia causing gout attacks. Xanthine oxidase was reported responsible for the overproduction of uric acid. MATERIAL AND METHODS: We intend to test in silico and in vitro, the inhibition effect of four vitamins against bovine milk xanthine oxidase (BXO). We performed Molecular docking with GOLD v4.0, and the biological activity prediction with the PASS server. The best-selected vitamins were chosen based on their best PLPchem score. The BXO constant Km and Vmax were determined in vitro, and then the vitamins were tested for their inhibition effect to BXO. Furthermore, the inhibition constant Ki of each inhibitor were determined using Dixon method, the vitamins chosen were vitamin E, vitamin B9, vitamin D3, and vitamin C. RESULTS: The in silico results show that the tested vitamins were the best inhibitors model with PLPchem scores up to 70 comparing to the control. The in vitro results show that BXO have a Km value of 163.55 µM with Vmax of 37 U, vitamins B9, E, C, and D3 were potent inhibitors to BXO with an IC50 of 34.10 ± 0.21, 36.68 ± 1.50, 39.01 ± 0.02, and 100.28 ± 0.33 µM, respectively comparing to the control (32.03 ± 0.73 µM). The kinetic study shows that all tested vitamins were Non-competitive inhibitors, the Ki values were 15 ± 1.76 µM, 29 ± 1.06 µM, 12 ± 1.41 µM, and 20 ± 0.71 µM, for respectively vitamins B9, E, C, and D3. CONCLUSION: The obtained results promise an excellent strategy using vitamins to enhance immunity, treat hyperuricemia, and minimize the usual drug side effects.

Exploring Structural Mechanism of COVID-19 Treatment with Glutathione as a Potential Peptide Inhibitor to the Main Protease: Molecular Dynamics Simulation and MM/PBSA Free Energy Calculations Study.

The 2019-novel coronavirus has unfolded everywhere in the world and obliged a billion human beings in open confinement, whereas many treatments, and vaccines have been proposed towards this pandemic. The main protease (Mpro) is an attractive drug target due to the fact that it is the essential protein for virus invasion. This research tests in silico the effect of five vitamins towards Mpro, by employing molecular docking (MD), molecular dynamics simulation (MDS) with molecular mechanics-Poisson-Boltzmann surface area (MM-PBSA) studies. To achieve this work, we have applied some software's as Autodock Vina, Discovery Studio Visualizer, APBS, and GROMACS. The inhibitors used were decided entirely on the basis of their importance in the production of red blood cells that prevent anemia, in lymphocyte immune system responses, in the regulation of reactive oxygen species production, such as tocopherol (vitamin E), thiamine (vitamin B1), pantothenic acid (vitamin B5), pyridoxine (vitamin B6), biotin (vitamin B7), and glutathione (GSH). The best inhibitor pose established at the highest repetition ratio (RR) and the minimal affinity energy value (MEV), then the best selected inhibitor was considered to MDS. The results indicate that GSH is the leading inhibitor model among the other tested vitamins in the active site of Mpro with a RR value of 94% and MEV of - 5.5 kcal/mol, its RMSD, RMSF, Rg, and hydrogen bonds show stability with Mpro. Furthermore, thiamine, biotin, and tocopherol are viewed as satisfying inhibitors to Mpro, but pyridoxine was observed as the weakest inhibitor. Based on our result, we could recommend the usage of glutathione and vitamin B family as a supportive strategy for feasible remedy of COVID-19 virus.