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Background: The plant-derived bioflavonoid amentoflavone has many important biological activities, among them remarkable antiviral effects, even against severe acute respiratory syndrome Coronavirus (SARS-CoV). It inhibits severe acute respiratory syndrome coronavirus (SARS-CoV) with an IC50 value of 8.3 M. (TMPRSS-2 activity is now thought to be the only factor necessary for cell entry and viral pathogenesis). In comparison, 3CLPRO is needed for COVID-19 replication and maturation during its life cycle. Aim: This study aims to perform an in silico study on amentoflavone activity against structural and non-structural severe acute respiratory syndrome coronavirus (SARS-CoV)-2 3-chymotrypsin-like protease (3CLPRO) and human transmembrane protease serine 2 (TMPRSS-2) proteins. Materials and Methods: Molecular docking studies were carried out using compounds against 3CLPRO and TMPRSS-2 proteins through the Swiss model, Uniport, PROCHECK, Swiss PDB viewer, PyMol, PyRx, and Desmond (Schrodinger package) computerized software.

Amygdalin possesses anticancer properties and induces apoptosis. Based on experimental studies the presence of amygdalin with cancer cells led to activate the caspase-3 and BAX and inhibits Bcl-2 and Poly (ADP-ribose) polymerase-1 (PARP-1) but without deep information on action mode of these activities. Herein, we leaped forward to examine the molecular dynamics of the bound amygdalin and free ligand proteins, to identify precise action (conformation changes in targeted proteins) of amygdalin through using double docking and molecular dynamics (MD) simulations for 50 ns time scale. The MD simulations revealed that the binding of amygdalin led to disrupting the interaction between the Bcl-2/BAX complex. We furthermore conducted MD simulation for Bcl-2/amygdalin to investigate the stability of the complex which is responsible for inhibition of Bcl-2. It has been obtained a stable Bcl-2/amygdalin complex during the 50 ns. The results give a detail explanation of how amygdalin activates BAX and inhibits Bcl-2. For caspase-3, the matter is different, we found that amygdalin led to disrupting the interaction of caspase-3’s two chains for intervals during 50 ns and then bind together repeatedly. The mechanism of caspase-3’s activation through switching by disrupt the interacts for periodic intervals manner. For PARP-1, the dynamics simulations results indicated amygdalin interacts with PARP-1’s binding site and forms stable interaction during simulation to render it inactive. Hence, amygdalin revealed a supernatural behavior through the MD simulations: it revealed a further clarification of the mystery amygdalin’s experimental action which can act as a multifunctional drug in the cancer therapeutics. Communicated by Ramaswamy H. Sarma

The ongoing pandemic situation of COVID-19 caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) poses a global threat to both the world economy and public health. Therefore, there is an urgent need to discover effective vaccines or drugs to fight against this virus. The flavonoids and their medicinal plant sources have already exhibited various biological effects, including antiviral, anti-inflammatory, antioxidant, etc. This study was designed to evaluate different flavonoids from medicinal plants as potential inhibitors against the spike protein (Sp) and main protease (Mpro) of SARS-CoV-2 using various computational approaches such as molecular docking, molecular dynamics. The binding affinity and inhibitory effects of all studied flavonoids were discussed and compared with some antiviral drugs that are currently being used in COVID-19 treatment namely favipiravir, lopinavir, and hydroxychloroquine, respectively. Among all studies flavonoids and proposed antiviral drugs, luteolin and mundulinol exhibited the highest binding affinity toward Mpro and Sp. Drug-likeness and ADMET studies revealed that the chosen flavonoids are safe and non-toxic. One hundred ns-MD simulations were implemented for luteolin-Mpro, mundulinol-Mpro, luteolin-Sp, and mundulinol-Sp complexes and the results revealed strong stability of these flavonoid-protein complexes. Furthermore, MM/PBSA confirms the stability of luteolin and mundulinol interactions within the active sites of this protein. In conclusion, our findings reveal that the promising activity of luteolin and mundulinol as inhibitors against COVID-19 via inhibiting the spike protein and major protease of SARS CoV-2, and we urge further research to achieve the clinical significance of our proposed molecular-based efficacy.

Dengue fever is a dangerous infectious endemic disease that affects over 100 nations worldwide, from Africa to the Western Pacific, and is caused by the dengue virus, which is transmitted to humans by an insect bite of Aedes aegypti. Millions of citizens have died as a result of dengue fever and dengue hemorrhagic fever across the globe. Envelope (E), serine protease (NS3), RNA-directed RNA polymerase (NS5), and non-structural protein 1 (NS1) are mostly required for cell proliferation and survival. Some of the diterpenoids and their derivatives produced by nature possess anti-dengue viral properties. The goal of the computational study was to scrutinize the effectiveness of diterpenoids and their derivatives against dengue viral proteins through in silico study. Methods: molecular docking was performed to analyze the binding affinity of compounds against four viral proteins: the envelope (E) protein, the NS1 protein, the NS3 protein, and the NS5 protein. Results: among the selected drug candidates, triptolide, stevioside, alepterolic acid, sphaeropsidin A, methyl dodovisate A, andrographolide, caesalacetal, and pyrimethamine have demonstrated moderate to good binding affinities (−8.0 to −9.4 kcal/mol) toward the selected proteins: E protein, NS3, NS5, and NS1 whereas pyrimethamine exerts −7.5, −6.3, −7.8, and −6.6 kcal/mol with viral proteins, respectively. Interestingly, the binding affinities of these lead compounds were better than those of an FDA-approved anti-viral medication (pyrimethamine), which is underused in dengue fever. Conclusion: we can conclude that diterpenoids can be considered as a possible anti-dengue medication option. However, in vivo investigation is recommended to back up the conclusions of this study.

Shigella dysenteriae type 1 is considered as an epidemic in different developing countries, which is responsible for the most severe form of bacterial dysentery. It habitually can develop to the most severe form of dysentery with deadly complications. Development of drugs against this disease is still ongoing. Therefore, we used in silico studies to screen the Inula britannica phytocompounds that are used in traditional Chinese and Kampo Medicines and have activities against different diseases. Spinacetin, eupatin, chrysoeriol and diosmetin were successfully passed through the docking-based screening and absorption, distribution, metabolism, excretion and toxicity (ADMET) filtration. The estimated docking affinities of eupatin, diosmetin, chrysoeriol and spinacetin with Dihydrofolate reductase type 1 (DHFR-1), were −6.5, −6.5, −6.3 and −6.1 kcal/mol, respectively. Which were selected for further investigations based on their favorable ADME/Tox characteristics. Then, the 100 ns molecular dynamics (MD) simulations of apo DHFR, spinacetin-DHFR, eupatin-DHFR, chrysoeriol-DHFR and diosmetin-DHFR complexes were carried out. The RMSD fluctuations of the spinacetin, eupatin, chrysoeriol and diosmetin inside the binding site were explored. Subsequently, the effect of binding Spinacetin, eupatin, chrysoeriol and diosmetin upon the dynamic stability of protein was assessed. Additionally, Principal Component Analysis (PCA) and Hydrogen bond analysis was performed for the apo protein and the protein ligand complexes. The results revealed that chrysoeriol and eupatin has good inhibitory effects against DHFR-1 as treatment for Shigella dysenteriae type when compared to other compounds under study. Hence this study implies that eupatin and chrysoeriol are a significantly potential drug like molecule for the treatment of Shigellosis and must undergo validation through in vivo and in vitro experiments. Communicated by Ramaswamy H. Sarma

Gastric cancer (GC) has limited effective treatment options and is followed up with biomarkers that have insufficient sensitivity and specificity. Recent studies on Collagen Type X Alpha 1 Chain (COL10A1) show that the COL10A1 gene may be a diagnostic and/or prognostic biomarker for different cancer types. Moreover, its relationship with the Sex determining Region Y (SRY)-related High-Mobility Group (HMG) box (SOX9) gene which is also a transcription factor, was discovered recently, and co-expression of these two genes are associated with the development of GC. However, to the best of our knowledge, there is no study in the literature on how potential damaging mutations in the SOX9 and COL10A1 genes can affect their interactions. The aim of this study is to investigate the interactions of wild-type and potentially damaging mutated structures of COL10A1 and SOX9 genes. Thus, outputs for drug development and therapeutic strategies for GC can be obtained. For this purpose, structure validation and energy minimization analyses as well as docking and binding affinity calculations were performed. As a result, it was found that all investigated mutations (P563S, I588L, T624A, H165R and N110T) increased the binding affinity between the COL10A1-SOX9 complex, especially the N110T and H165R mutants in SOX9. As a conclusion, the N110T and H165R mutants in SOX9 may contribute to tumor progression. Therefore, it is important to consider these mutations for future therapeutic strategies.Communicated by Ramaswamy H. Sarma.

The levels of reactive oxygen species (ROS) are tightly controlled and regulated by Nuclear Factor Erythroid-2-Like 2 (Nrf2) transcription factor, which is the main regulator of antioxidant responses and its suppressor protein Kelch-like ECH-associated protein 1 (Keap1). Our previous study has identified six novel changes in Nrf2/Keap1 pathway in pediatric ALL, which were described for the first time. These changes in the pathway are likely to alter the evolutionary process of amino acids and cause structural changes in the final products of genes. In this study, we aimed to compare the pathogenicity of eight determined mutations reported in our previous study by utilizing different programs with different algorithms and molecular dynamics simulation. Since it is too difficult to handle each existing mutation in a wet laboratory

SARS-CoV-2 is a new generation of coronavirus, which was first determined in Wuhan, China, in December 2019. So far, however, there no effective treatment has been found to stop this new generation of coronavirus but discovering of the crystal structure of SARS-CoV-2 main protease (SARS-CoV-2 Mpro) may facilitate searching for new therapies for SARS-COV-2. The aim was to assess the effectiveness of available FDA approved drugs which can construct a covalent bond with Cys145 inside binding site SARS-CoV-2 main protease by using covalent docking screening. We conducted the covdock module MMGBSA module in the Schrodinger suite 2020-1, to examine the covalent bonding utilizing. Besides, we submitted the top three drugs to molecular dynamics simulations via Gromacs 2018.1. The covalent docking showed that saquinavir, ritonavir, remdesivir, delavirdine, cefuroxime axetil, oseltamivir and prevacid have the highest binding energies MMGBSA of –72.17, −72.02, −65.19, −57.65, −54.25, −51.8, and −51.14 kcal/mol, respectively. The 50 ns molecular dynamics simulation was conducted for saquinavir, ritonavir and remdesivir to evaluate the stability of these drugs inside the binding pocket of SARS-CoV-2 main protease. The current study provides a powerful in silico results, means for rapid screening of drugs as anti-protease medications and recommend that the above-mentioned drugs can be used in the treatment of SARS-CoV-2 in combined or sole therapy. Communicated by Ramaswamy H. Sarma

The research aimed to investigate the anti-inflammatory effect of 4-hydroxy coumarin derivatives on inflammatory response in rats and to estimate the toxicity of enumerated compounds (3-11) following acute exposure. Toxicity report was collected by oral dosing administered individually to rats on a scale of 10-3000 mg/kg, while an indication of toxicity was observed for ten days following the last given dose. The response to inflammation was estimated using the model of xylene-induced edema and the model of carrageenan-inflammation of the paw. Compounds were administered orally to animals at a once-daily dose for seven sequential days. Molecular docking studies with COX-II enzyme were used to explain deeply the activity of synthesized compounds. Furthermore, the in-silico results were quite consistent with biological activity. Interestingly, compounds 5 and 10 showing the highest binding points (lower values). Therefore, the molecular dynamics simulation study of the most active compounds 5 and 10 was performed.

Background: Depressive disorder is a recurrent illness that affects large numbers of the general population worldwide. In recent years, the goal of depression treatment has moved from symptomatic response to that of full remission. However, treatment-resistant depression is a major challenge in the treatment of depression or depression-related disorders. Consensus opinion, therefore, suggests that effective combined aggressive initial treatment is the most appropriate strategy. Objectives: This study aimed to evaluate the effects of quercetin (QUR) and/or ascorbic acid (AA) on Phenobarbital-induced sleeping mice. Methods: QUR (50 mg/kg) and/or AA (25 mg/kg) with or without intraperitoneally pre-treated with GABA receptor agonist (diazepam: 2 mg/kg, i.p.) or antagonist (Flumazenil: 2.5 mg/kg, i.p.) to underscore the effects, as well as the possible involvement of the GABA receptor in the modulatory action of QUR and AA in sleeping mice. Additionally, an in silico study was undertaken to predict the involvement of GABA receptors in the sleep mechanism. Results: Findings suggest that the pretreatment of QUR and AA modulated the onset and duration of action of the standard drugs in experimental animals. The acute administration of QUR and/or AA significantly (p &lt, 0.05) reversed the DZP-mediated onset of action and slightly reversed the duration of sleep time in comparison to the vehicle (control) group. A further combination of QUR or AA with the FLU resulted in an enhancement of the onset of action while reducing the duration of action, suggesting a FLU-like effect on the test animals. In in silico studies, AA and QUR showed good to moderate binding affinities with GABAA and GABAB receptors. Conclusions: Both QUR and AA produced a stimulatory-like effect on mice, possibly through the GABAA and GABAB receptor interaction pathways. Further studies are necessary to verify this activity and clarify the exact mechanism of action(s) involved.