Investigating the potent TOPO IIα inhibitors in breast cancer through the study of computational drug discovery research approaches.

Breast cancer (BC) is the second-leading cause of cancer after lung cancer. The disease has affected millions of people and resulted in many deaths. In the metastasis of breast cancer cells, Topoisomerase IIα plays a vital role. Therefore, this investigation aims to identify potential flavonoid compounds against BC by inhibiting this enzyme at an early stage. Based on previous studies, we selected and screened several plant-derived flavonoid compounds with potential anti-breast cancer activity using PyRx 0.8 and Schrodinger applications for preliminary molecular docking: the highest docking scores of Myricetin (-11.6 kcal/mol) and Quercetin (-10.0 kcal/mol). Next, we evaluated the top four compounds on the Way2Drug server to complete the cytotoxicity evaluation, which demonstrated anti-cancer and anti-breast cancer activity in various cell lines. According to pharmacokinetics studies, four compounds exhibited outstanding values and functioned similar to drug-like molecules. Moreover, Myricetin, Quercetin, and Morin displayed the highest number of hydrogen bonds, with the corresponding receptor forming residues asn120, thr147, and lys168. The protein-ligand complexes were validated using the Desmond simulator, and their data were compared to the anti-breast cancer drug Doxorubicin. In the simulation analysis, various parameters were evaluated, including RMSD, RMSF, Rg, SASA, MolSA, PSA, and hydrogen bond interaction. Finally, validated our dynamic simulation result with MM-GBSA operation, and Myricetin and Quercetin had the greatest score of -72.74344651, -66.66771823 kcal/mol, which is outstanding than the control drug. Hence, the computational research approach determined that Myricetin, Quercetin, and Morin could be industrially developed for the alternative treatment of breast cancer following additional confirmation from animal and cell line studies.

Amentoflavone derivatives significantly act towards the main protease (3CLPRO/MPRO) of SARS-CoV-2: in silico admet profiling, molecular docking, molecular dynamics simulation, network pharmacology.

SARS-CoV-2 is the foremost culprit of the novel coronavirus disease 2019 (nCoV-19 and/or simply COVID-19) and poses a threat to the continued life of humans on the planet and create pandemic issue globally. The 3-chymotrypsin-like protease (MPRO or 3CLPRO) is the crucial protease enzyme of SARS-CoV-2, which directly involves the processing and release of translated non-structural proteins (nsps), and therefore involves the development of virus pathogenesis along with outbreak the forecasting of COVID-19 symptoms. Moreover, SARS-CoV-2 infections can be inhibited by plant-derived chemicals like amentoflavone derivatives, which could be used to develop an anti-COVID-19 drug. Our research study is designed to conduct an in silico analysis on derivatives of amentoflavone (isoginkgetin, putraflavone, 4''''''-methylamentoflavone, bilobetin, ginkgetin, sotetsuflavone, sequoiaflavone, heveaflavone, kayaflavone, and sciadopitysin) for targeting the non-structural protein of SARS-CoV-2, and subsequently further validate to confirm their antiviral ability. To conduct all the in silico experiments with the derivatives of amentoflavone against the MPRO protein, both computerized tools and online servers were applied; notably the software used is UCSF Chimera (version 1.14), PyRx, PyMoL, BIOVIA Discovery Studio tool (version 4.5), YASARA (dynamics simulator), and Cytoscape. Besides, as part of the online tools, the SwissDME and pKCSM were employed. The research study was proposed to implement molecular docking investigations utilizing compounds that were found to be effective against the viral primary protease (MPRO). MPRO protein interacted strongly with 10 amentoflavone derivatives. Every time, amentoflavone compounds outperformed the FDA-approved antiviral medicine that is currently underused in COVID-19 in terms of binding affinity (- 8.9, - 9.4, - 9.7, - 9.1, - 9.3, - 9.0, - 9.7, - 9.3, - 8.8, and - 9.0 kcal/mol, respectively). The best-selected derivatives of amentoflavone also possessed potential results in 100 ns molecular dynamic simulation (MDS) validation. It is conceivable that based on our in silico research these selected amentoflavone derivatives more precisely 4''''''-methylamentoflavone, ginkgetin, and sequoiaflavone have potential for serving as promising lead drugs against SARS-CoV-2 infection. In consequence, it is recommended that additional in vitro as well as in vivo research studies have to be conducted to support the conclusions of this current research study.

Natural flavonoids effectively block the CD81 receptor of hepatocytes and inhibit HCV infection: a computational drug development approach.

Hepatitis C virus (HCV) infection is a major public health concern, and almost two million people are infected per year globally. This is occurred by the diverse spectrum of viral genotypes, which are directly associated with chronic liver disease (fibrosis, and cirrhosis). Indeed, the viral genome encodes three principal proteins as sequentially core, E1, and E2. Both E1 and E2 proteins play a crucial role in the attachment of the host system, but E2 plays a more fundamental role in attachment. The researchers have found the "E2-CD81 complex" at the entry site, and therefore, CD81 is the key receptor for HCV entrance in both humans, and chimpanzees. So, the researchers are trying to block the host CD81 receptor and halt the virus entry within the cellular system via plant-derived compounds. Perhaps that is why the current research protocol is designed to perform an in silico analysis of the flavonoid compounds for targeting the tetraspanin CD81 receptor of hepatocytes. To find out the best flavonoid compounds from our library, web-based tools (Swiss ADME, pKCSM), as well as computerized tools like the PyRx, PyMOL, BIOVIA Discovery Studio Visualizer, Ligplot+ V2.2, and YASARA were employed. For molecular docking studies, the flavonoid compounds docked with the targeted CD81 protein, and herein, the best-outperformed compounds are Taxifolin, Myricetin, Puerarin, Quercetin, and (-)-Epicatechin, and outstanding binding affinities are sequentially - 7.5, - 7.9, - 8.2, - 8.4, and - 8.5 kcal/mol, respectively. These compounds have possessed more interactions with the targeted protein. To validate the post docking data, we analyzed both 100 ns molecular dynamic simulation, and MM-PBSA via the YASARA simulator, and finally finds the more significant outcomes. It is concluded that in the future, these compounds may become one of the most important alternative antiviral agents in the fight against HCV infection. It is suggested that further in vivo, and in vitro research studies should be done to support the conclusions of this in silico research workflow.

The efficacy of natural bioactive compounds against prostate cancer: Molecular targets and synergistic activities.

Globally, prostate cancer (PCa) is regarded as a challenging health issue, and the number of PCa patients continues to rise despite the availability of effective treatments in recent decades. The current therapy with chemotherapeutic drugs has been largely ineffective due to multidrug resistance and the conventional treatment has restricted drug accessibility to malignant tissues, necessitating a higher dosage resulting in increased cytotoxicity. Plant-derived bioactive compounds have recently attracted a great deal of attention in the field of PCa treatment due to their potent effects on several molecular targets and synergistic effects with anti-PCa drugs. This review emphasizes the molecular mechanism of phytochemicals on PCa cells, the synergistic effects of compound-drug interactions, and stem cell targeting for PCa treatment. Some potential compounds, such as curcumin, phenethyl-isothiocyanate, fisetin, baicalein, berberine, lutein, and many others, exert an anti-PCa effect via inhibiting proliferation, metastasis, cell cycle progression, and normal apoptosis pathways. In addition, multiple studies have demonstrated that the isolated natural compounds: d-limonene, paeonol, lanreotide, artesunate, and bicalutamide have potential synergistic effects. Further, a significant number of natural compounds effectively target PCa stem cells. However, further high-quality studies are needed to firmly establish the clinical efficacy of these phytochemicals against PCa.

Study of MDM2 as Prognostic Biomarker in Brain-LGG Cancer and Bioactive Phytochemicals Inhibit the p53-MDM2 Pathway: A Computational Drug Development Approach.

An evaluation of the expression and predictive significance of the MDM2 gene in brain lower-grade glioma (LGG) cancer was carried out using onco-informatics pipelines. Several transcriptome servers were used to measure the differential expression of the targeted MDM2 gene and search mutations and copy number variations. GENT2, Gene Expression Profiling Interactive Analysis, Onco-Lnc, and PrognoScan were used to figure out the survival rate of LGG cancer patients. The protein-protein interaction networks between MDM2 gene and its co-expressed genes were constructed by Gene-MANIA tool. Identified bioactive phytochemicals were evaluated through molecular docking using Schrödinger Suite Software, with the MDM2 (PDB ID: 1RV1) target. Protein-ligand interactions were observed with key residues of the macromolecular target. A molecular dynamics simulation of the novel bioactive compounds with the targeted protein was performed. Phytochemicals targeting MDM2 protein, such as Taxifolin and (-)-Epicatechin, have been shown with more highly stable results as compared to the control drug, and hence, concluded that phytochemicals with bioactive potential might be alternative therapeutic options for the management of LGG patients. Our once informatics-based designed pipeline has indicated that the MDM2 gene may have been a predictive biomarker for LGG cancer and selected phytochemicals possessed outstanding interaction results within the macromolecular target's active site after utilizing in silico approaches. In vitro and in vivo experiments are recommended to confirm these outcomes.

A Comprehensive Analysis and Anti-Cancer Activities of Quercetin in ROS-Mediated Cancer and Cancer Stem Cells.

Reactive oxygen species (ROS) induce carcinogenesis by causing genetic mutations, activating oncogenes, and increasing oxidative stress, all of which affect cell proliferation, survival, and apoptosis. When compared to normal cells, cancer cells have higher levels of ROS, and they are responsible for the maintenance of the cancer phenotype; this unique feature in cancer cells may, therefore, be exploited for targeted therapy. Quercetin (QC), a plant-derived bioflavonoid, is known for its ROS scavenging properties and was recently discovered to have various antitumor properties in a variety of solid tumors. Adaptive stress responses may be induced by persistent ROS stress, allowing cancer cells to survive with high levels of ROS while maintaining cellular viability. However, large amounts of ROS make cancer cells extremely susceptible to quercetin, one of the most available dietary flavonoids. Because of the molecular and metabolic distinctions between malignant and normal cells, targeting ROS metabolism might help overcome medication resistance and achieve therapeutic selectivity while having little or no effect on normal cells. The powerful bioactivity and modulatory role of quercetin has prompted extensive research into the chemical, which has identified a number of pathways that potentially work together to prevent cancer, alongside, QC has a great number of evidences to use as a therapeutic agent in cancer stem cells. This current study has broadly demonstrated the function-mechanistic relationship of quercetin and how it regulates ROS generation to kill cancer and cancer stem cells. Here, we have revealed the regulation and production of ROS in normal cells and cancer cells with a certain signaling mechanism. We demonstrated the specific molecular mechanisms of quercetin including MAPK/ERK1/2, p53, JAK/STAT and TRAIL, AMPKα1/ASK1/p38, RAGE/PI3K/AKT/mTOR axis, HMGB1 and NF-κB, Nrf2-induced signaling pathways and certain cell cycle arrest in cancer cell death, and how they regulate the specific cancer signaling pathways as long-searched cancer therapeutics.

Diterpenes/Diterpenoids and Their Derivatives as Potential Bioactive Leads against Dengue Virus: A Computational and Network Pharmacology Study.

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.

Baicalein as Promising Anticancer Agent: A Comprehensive Analysis on Molecular Mechanisms and Therapeutic Perspectives.

Despite significant therapeutic advancements for cancer, an atrocious global burden (for example, health and economic) and radio- and chemo-resistance limit their effectiveness and result in unfavorable health consequences. Natural compounds are generally considered safer than synthetic drugs, and their use in cancer treatment alone, or in combination with conventional therapies, is increasingly becoming accepted. Interesting outcomes from pre-clinical trials using Baicalein in combination with conventional medicines have been reported, and some of them have also undergone clinical trials in later stages. As a result, we investigated the prospects of Baicalein, a naturally occurring substance extracted from the stems of Scutellaria baicalensis Georgi and Oroxylum indicum Kurz, which targets a wide range of molecular changes that are involved in cancer development. In other words, this review is primarily driven by the findings from studies of Baicalein therapy in several cancer cell populations based on promising pre-clinical research. The modifications of numerous signal transduction mechanisms and transcriptional agents have been highlighted as the major players for Baicalein's anti-malignant properties at the micro level. These include AKT serine/threonine protein kinase B (AKT) as well as PI3K/Akt/mTOR, matrix metalloproteinases-2 & 9 (MMP-2 & 9), Wnt/-catenin, Poly(ADP-ribose) polymerase (PARP), Mitogen-activated protein kinase (MAPK), NF-κB, Caspase-3/8/9, Smad4, Notch 1/Hes, Signal transducer and activator of transcription 3 (STAT3), Nuclear factor erythroid 2-related factor 2 (Nrf2)/Kelch-like ECH-associated protein-1 (Keap 1), Adenosine monophosphate-activated protein kinase (AMPK), Src/Id1, ROS signaling, miR 183/ezrin, and Sonic hedgehog (Shh) signaling cascades. The promise of Baicalein as an anti-inflammatory to anti-apoptotic/anti-angiogenic/anti-metastatic medicinal element for treating various malignancies and its capability to inhibit malignant stem cells, evidence of synergistic effects, and design of nanomedicine-based drugs are altogether well supported by the data presented in this review study.

Advanced implications of nanotechnology in disease control and environmental perspectives.

Nanotechnology encompasses a wide range of devices derived from biology, engineering, chemistry, and physics, and this scientific field is composed of great collaboration among researchers from several fields. It has diverse implications notably smart sensing technologies, effective disease diagnosis, and sometimes used in treatment. In medical science, the implications of nanotechnology include the development of elements and devices that interact with the body at subcellular (i.e., molecular) levels exhibiting high sensitivity and specificity. There is a plethora of new chances for medical science and disease treatment to be discovered and exploited in the rapidly developing field of nanotechnology. In different sectors, nanomaterials are used just because of their special characteristics. Their large surface area of them enables higher reactivity with greater efficiency. Furthermore, special surface chemistry is displayed by nanomaterials which compare to conventional materials and facilitate the nanomaterials to decrease pollutants efficiently. Recently, nanomaterials are used in some countries to reduce the levels of contaminants in water, air, and soil. Moreover, nanomaterials are used in the cosmetics and medical industry, and it develops the drug discovery (DD) system. Among a huge number of nanomaterials, Cu, Ag, TiO2, ZnO, Fe3O4, and carbon nanotubes (CNTs) are extensively used in different industries for various purposes. This extensive review study has introduced the major scientific and technical features of nanotechnology, as well as some possible clinical applications and positive feedback in environmental waste management and drug delivery systems.

Catabolic profiling of selective enzymes in the saccharification of non-food lignocellulose parts of biomass into functional edible sugars and bioenergy: An in silico bioprospecting.

Objectives: The research aims to analyze the catabolic strength of different hydrolytic enzymes in assessing the biological conversion potential of lignocellulose parts of agricultural biomass wastes into functional edible sugars and biofuels. Materials and Methods: The enzymes' hydrolytic properties-versatile peroxidase, manganese peroxidase, and lignin peroxidase were used to identify their complexing strength with the lignin substrate, whereas endoglucanase cel12A, acidocaldarius cellulase, and Melanocarpus albomyces endoglucanase were tested on the cellulose gel substrate. Because the biodegradation properties are heavily influenced by the "enzyme-substrate complexing energy level," proper molecular optimization and energy minimization of the enzymes and substrates were carried out, as well as the identification of the enzyme's active sites prior to complexing.comprehensive molecular dynamic simulation was run to study their-alpha carbon, root-mean-square deviation (Å), molecular surface area (Å2), root-mean-square fluctuation (Å), radius of gyration (nm), hydrogen bonds with hydrophobic interactions, and solvent accessible surface area (Å2) values for 50 ns. The simulated data mining was conducted using advanced programming algorithms to establish the final enzyme-substrate complexing strength in binding and catalysis. Results: Among the lignin-degrading enzymes, versatile peroxidase shows promising catalytic activity with the best docking pose and significant values in all the dynamic simulation parameters. Similarly, Melanocarpus albomyces endoglucanase shows the best activity in all aspects of molecular docking and dynamics among the cellulose-degrading enzymes. Conclusion: The lignin content of biomass wastes can be degraded into cellulose and hemicellulose using lignin-degrading enzymes. The cellulose can be further degraded into glucose and xylose sugars following the cellulose-degrading enzyme activity. These sugars can be further degraded into biofuel through anaerobic fermentation. Systematic bioconversion of the lignocellulosic components can ensure sustainable biomass management, creating an alternative food and energy source for human beings to face the challenges of global hunger where the enzymes can pave the way.

Point-specific interactions of isovitexin with the neighboring amino acid residues of the hACE2 receptor as a targeted therapeutic agent in suppressing the SARS-CoV-2 influx mechanism.

Objective: Despite the development of several vaccines against severe acute respiratory syndrome coronavirus-2, the need for an additional prophylactic agent is evident. In recent in silico studies, isovitexin exhibited a higher binding affinity against the human angiotensin converting-enzyme 2 (hACE2) receptor than existing antiviral drugs. The research aimed to find out the point specificity of isovitexin for the hACE2 receptor and to assess its therapeutic potential, depending on the stability of the isovitexin-hACE2 complex. Materials and Methods: The pharmacokinetic profile of isovitexin was analyzed. The crystal structure of the hACE2 receptor and the ligand isovitexin were docked to form a ligand-protein complex following molecular optimization. To determine the isovitexin-hACE2 complex stability, their binding affinity, hydrogen bonding, and hydrophobic interactions were studied. Lastly, the root mean square deviation (RMSD), root mean square fluctuation, solvent accessible surface area, molecular surface area, radius of gyration (Rg), polar surface area, and principal component analysis values were found by simulating the complex with molecular dynamic (MD). Results: The predicted Lethal dose50 for isovitexin was 2.56 mol/kg, with an acceptable maximum tolerated dose and no hepatotoxicity or AMES toxicity. Interactions with the amino acid residues Thr371, Asp367, Glu406, Pro346, His345, Phe274, Tyr515, Glu375, Thr347, Glu402, and His374 of the hACE2 protein were required for the high binding affinity and specificity of isovitexin. Based on what was learned from the MD simulation, the hACE2 receptor-blocking properties of isovitexin were looked at. Conclusions: Isovitexin is a phytochemical with a reasonable bioactivity and safety profile for use in humans, and it can potentially be used as a hACE2-specific therapeutic to inhibit COVID-19 infection.

An In-Silico Identification of Potential Flavonoids against Kidney Fibrosis Targeting TGFßR-1.

Fibrosis is a hallmark of progressive kidney diseases. The overexpression of profibrotic cytokine, namely transforming growth factor ß (TGF-ß) due to excessive inflammation and tissue damage, induces kidney fibrosis. The inhibition of TGF-ß signaling is markedly limited in experimental disease models. Targeting TGF-ß signaling, therefore, offers a prospective strategy for the management of kidney fibrosis. Presently, the marketed drugs have numerous side effects, but plant-derived compounds are relatively safer and more cost-effective. In this study, TGFßR-1 was targeted to identify the lead compounds among flavonoids using various computational approaches, such as ADME/T (absorption, distribution, metabolism, and excretion/toxicity) analysis, molecular docking, and molecular dynamics simulation. ADME/T screening identified a total of 31 flavonoids with drug-like properties of 31 compounds, a total of 5 compounds showed a higher binding affinity to TGFßR-1, with Epicatechin, Fisetin, and Luteolin ranking at the top three (-13.58, -13.17, and -10.50 kcal/mol, respectively), which are comparable to the control drug linagliptin (-9.074 kcal/mol). The compounds also exhibited outstanding protein-ligand interactions. The molecular dynamic simulations revealed a stable interaction of these compounds with the binding site of TGFßR-1. These findings indicate that flavonoids, particularly Epicatechin, Fisetin, and Luteolin, may compete with the ligand-binding site of TGFßR-1, suggesting that these compounds can be further evaluated for the development of potential therapeutics against kidney fibrosis. Further, in-vitro and in-vivo studies are recommended to support the current findings.

Investigating the Anticancer Potential of Salvicine as a Modulator of Topoisomerase II and ROS Signaling Cascade.

Salvicine is a new diterpenoid quinone substance from a natural source, specifically in a Chinese herb. It has powerful growth-controlling abilities against a broad range of human cancer cells in both in vitro and in vivo environments. A significant inhibitory effect of salvicine on multidrug-resistant (MDR) cells has also been discovered. Several research studies have examined the activities of salvicine on topoisomerase II (Topo II) by inducing reactive oxygen species (ROS) signaling. As opposed to the well-known Topo II toxin etoposide, salvicine mostly decreases the catalytic activity with a negligible DNA breakage effect, as revealed by several enzymatic experiments. Interestingly, salvicine dramatically reduces lung metastatic formation in the MDA-MB-435 orthotopic lung cancer cell line. Recent investigations have established that salvicine is a new non-intercalative Topo II toxin by interacting with the ATPase domains, increasing DNA-Topo II interaction, and suppressing DNA relegation and ATP hydrolysis. In addition, investigations have revealed that salvicine-induced ROS play a critical role in the anticancer-mediated signaling pathway, involving Topo II suppression, DNA damage, overcoming multidrug resistance, and tumor cell adhesion suppression, among other things. In the current study, we demonstrate the role of salvicine in regulating the ROS signaling pathway and the DNA damage response (DDR) in suppressing the progression of cancer cells. We depict the mechanism of action of salvicine in suppressing the DNA-Topo II complex through ROS induction along with a brief discussion of the anticancer perspective of salvicine.

A Comprehensive Discussion in Vaginal Cancer Based on Mechanisms, Treatments, Risk Factors and Prevention.

Vaginal cancer is a rare and uncommon disease that is rarely discussed. Although vaginal cancer traditionally occurs in older postmenopausal women, the incidence of high-risk human papillomavirus (HPV)-induced cancers is increasing in younger women. Cervical cancer cells contain high-risk human papillomavirus (HPV) E6 and E7 proteins and inhibiting HPV gene expression leads the cells to stop proliferating and enter senescence. As E6, and E7 protein promoted the carcinogenesis mechanism, and here not only regulate the cellular degradation of P53, and pRb but also enhances the cell proliferation along with E6 protein targets the p53 for breakdown and subsequently promote the apoptotic cell death, and DNA repair inhibition, that is indispensable to the continue the lifecycle of the HPV. As a synchronous or metachronous tumor, vaginal cancer is frequently found in combination with cervical cancer. It is uncertain what causes invasive female vaginal organ cancer. HPV type 16 is the most often isolated HPV type in female vaginal organ cancers. Due to cancer's rarity, case studies have provided the majority of etiologic findings. Many findings demonstrate that ring pessaries, chronic vaginitis, sexual behavior, birth trauma, obesity, vaginal chemical exposure, and viruses are all risk factors. Because of insufficient understanding and disease findings, we are trying to find the disease's mechanism with the available data. We also address different risk factors, therapy at various stages, diagnosis, and management of vaginal cancer in this review.

Molecular optimization, docking, and dynamic simulation profiling of selective aromatic phytochemical ligands in blocking the SARS-CoV-2 S protein attachment to ACE2 receptor: an in silico approach of targeted drug designing.

OBJECTIVES: The comprehensive in silico study aims to figure out the most effective aromatic phytochemical ligands among a number from a library, considering their pharmacokinetic efficacies in blocking "angiotensin-converting enzyme 2 (ACE2) receptor-severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) S protein" complex formation as part of a target-specific drug designing. MATERIALS AND METHODS: A library of 57 aromatic pharmacophore phytochemical ligands was prepared from where the top five ligands depending on Absorption, Distribution, Metabolism, Excretion, and Toxicity (ADMET) and quantitative structure-activity relationship (QSAR)-based pharmacokinetic properties were considered. The selected ligands were optimized for commencing molecular docking and dynamic simulation as a complex with the ACE2 receptor to compare their blocking efficacy with the control drug. The ligand-receptor complexes' accuracy in preventing the Spike (S) protein of SARS-CoV-2 penetration inside the host cells has been analyzed through hydrogen-hydrophobic bond interactions, principal component analysis (PCA), root mean square deviation (RMSD), root mean square fluctuation (RMSF), and B-Factor. Advanced in silico programming language and bioanalytical software were used for high throughput and authentic results. RESULTS: ADMET and QSAR revealed Rhamnetin, Lactupicrin, Rhinacanthin D, Flemiflavanone D, and Exiguaflavanone A as the ligands of our interest to be compared with the control Cassiarin D. According to the molecular docking binding affinity to block ACE2 receptor, the efficiency mountings were Rhinacanthin D > Flemiflavanone D > Lactupicrin > Exiguaflavanone A > Rhamnetin. The binding affinity of the Cassiarin D-ACE2 complex was (-10.2 KJ/mol) found inferior to the Rhinacanthin D-ACE2 complex (-10.8 KJ/mol), referring to Rhinacanthin D as a more stable candidate to use as drugs. The RMSD values of protein-ligand complexes evaluated according to their structural conformation and stable binding pose ranged between 0.1~2.1 Å. The B-factor showed that very few loops were present in the protein structure. The RMSF peak fluctuation regions ranged 5-250, predicting efficient ligand-receptor interactions. CONCLUSION: The experiment sequentially measures all the parameters required in referring to any pharmacophore as a drug, considering which all aromatic components analyzed in the study can strongly be predicted as target-specific medication against the novel coronavirus 2019 infection.

Quercetin and/or Ascorbic Acid Modulatory Effect on Phenobarbital-Induced Sleeping Mice Possibly through GABAA and GABAB Receptor Interaction Pathway.

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. This study aimed to evaluate the effects of quercetin (QUR) and/or ascorbic acid (AA) on Phenobarbital-induced sleeping mice. 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. 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 < 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. 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.

Analysis of SYK Gene as a Prognostic Biomarker and Suggested Potential Bioactive Phytochemicals as an Alternative Therapeutic Option for Colorectal Cancer: An In-Silico Pharmaco-Informatics Investigation.

BACKGROUND: SYK gene regulates the expression of SYK kinase (Spleen tyrosine kinase), an important non-receptor protein-tyrosine kinase for immunological receptor-mediated signaling, which is also considered a tumor growth metastasis initiator. An onco-informatics analysis was adopted to evaluate the expression and prognostic value of the SYK gene in colorectal cancer (CRC), the third most fatal cancer type; of late, it may be a biomarker as another targeted site for CRC. In addition, identify the potential phytochemicals that may inhibit the overexpression of the SYK kinase protein and minimize the human CRC. MATERIALS & METHODS: The differential expression of the SYK gene was analyzed using several transcriptomic databases, including Oncomine, UALCAN, GENT2, and GEPIA2. The server cBioPortal was used to analyze the mutations and copy number alterations, whereas GENT2, Gene Expression Profiling Interactive Analysis (GEPIA), Onco-Lnc, and PrognoScan were used to examine the survival rate. The protein-protein interaction network of SYK kinase and its co-expressed genes was conducted via Gene-MANIA. Considering the SYK kinase may be the targeted site, the selected phytochemicals were assessed by molecular docking using PyRx 0.8 packages. Molecular interactions were also observed by following the Ligplot+ version 2.2. YASARA molecular dynamics simulator was applied for the post-validation of the selected phytochemicals. RESULTS: Our result reveals an increased level of mRNA expression of the SYK gene in colorectal adenocarcinoma (COAD) samples compared to those in normal tissues. A significant methylation level and various genetic alterations recurrence of the SYK gene were analyzed where the fluctuation of the SYK alteration frequency was detected across different CRC studies. As a result, a lower level of SYK expression was related to higher chances of survival. This was evidenced by multiple bioinformatics platforms and web resources, which demonstrated that the SYK gene can be a potential biomarker for CRC. In this study, aromatic phytochemicals, such as kaempferol and glabridin that target the macromolecule (SYK kinase), showed higher stability than the controls, and we have estimated that these bioactive potential phytochemicals might be a useful option for CRC patients after the clinical trial. CONCLUSIONS: Our onco-informatics investigation suggests that the SYK gene can be a potential prognostic biomarker of CRC. On the contrary, SYK kinase would be a major target, and all selected compounds were validated against the protein using in-silico drug design approaches. Here, more in vitro and in vivo analysis is required for targeting SYK protein in CRC.

Ethnomedicinal Use, Phytochemistry, and Pharmacology of Xylocarpus granatum J. Koenig.

The mangrove plants are the potential sources of foods and remedies for people living in the forests and nearby communities. Xylocarpus granatum J. Koenig is traditionally used to treat various diseases including diarrhea, cholera, dysentery, fever, malaria, and viral infections, among others. To summarize critically the taxonomy, ethnomedicinal, phytochemistry, and pharmacological activities of X. granatum, information was collected from different databases. An up-to-date search (till June 2020) was carried out with the help of various scientific web resources from databases such as PubMed, Science Direct, Google Scholar, and various patent offices (e.g., WIPO, CIPO, and USPTO) using the keywords "Xylocarpus granatum" and then paired with ethnomedicinal use and phytochemical, phytochemistry, and pharmacological activity (in vitro, ex vivo, and in vivo studies). Findings revealed that seeds, fruits, stem bark, leaf, and twigs of X. granatum exhibited a wide range of key phytochemicals including limonoids, phragmalin, limonoid-based alkaloids, mexicanolides, protolimonoids, flavonols, and lactones. The plant possessed potent antioxidant, anticancer, antidiabetic, antimicrobial, antimalarial, antifeedant, and neuroprotective activities. No clinical studies have been reported in the databases. Ethnomedicinal assessment indicated the application of X. granatum in various fields of medical science specially to treat various human ailments, and this was attributed to the presence of enormous alkaloids as confirmed by pharmacological studies. However, to understand the mechanism of action in-depth studies are required. In view of these findings, more research is necessary to explore and characterize the chemical compounds and toxicological aspects of this medicinal mangrove plant. Overall, it can be stated that X. granatum may be one of the hopeful medicinal herbs for the treatment of various diseases in human beings.

Candidate antiviral drugs for COVID-19 and their environmental implications: a comprehensive analysis.

Emerging from Wuhan, China, SARS-CoV-2 is the new global threat that killed millions of people, and many are still suffering. This pandemic has not only affected people but also caused economic crisis throughout the world. Researchers have shown good progress in revealing the molecular insights of SARS-CoV-2 pathogenesis and developing vaccines, but effective treatment against SARS-CoV-2-infected patients are yet to be found. Several vaccines are available and used in many countries, while many others are still in clinical or preclinical studies. However, this involves a long-term process, considering the safety procedures and requirements and their long-term protection capacity and in different age groups are still questionable. Therefore, at present, the drug repurposing of the existing therapeutics previously designed against other viral diseases seems to be the only practical approach to mitigate the current situation. The safety of most of these therapeutic agents has already been tested. Recent clinical reports revealed promising therapeutic efficiency of several drugs such as remdesivir, tenofovir disoproxil fumarate, azithromycin, lopinavir/ritonavir, chloroquine, baricitinib, and cepharanthine. Besides, plasma therapies were used to treat patients and prevent fatal outcomes. Thus, in this article, we have summarized the epidemiological and clinical data from several clinical trials conducted since the beginning of the pandemic, emphasizing the efficiency of the known agents against SARS-CoV-2 and their harmful side effects on the human body as well as their environmental implications. This review shows a clear overview of the current pharmaceutical perspective on COVID-19 treatment.

Active site-specific quantum tunneling of hACE2 receptor to assess its complexing poses with selective bioactive compounds in co-suppressing SARS-CoV-2 influx and subsequent cardiac injury.

OBJECTIVE: This research aims to study the target specificity of selective bioactive compounds in complexing with the human angiotensin-converting enzyme (hACE2) receptor to impede the severe acute respiratory syndrome coronavirus 2 influx mechanism resulting in cardiac injury and depending on the receptor's active site properties and quantum tunneling. MATERIALS AND METHODS: A library of 120 phytochemical ligands was prepared, from which 5 were selected considering their absorption, distribution, metabolism, and excretion (ADMET) and quantitative structure-activity relationship (QSAR) profiles. The protein active sites and belonging quantum tunnels were defined to conduct supramolecular docking of the aforementioned ligands. The hydrogen bond formation and hydrophobic interactions between the ligand-receptor complexes were studied following the molecular docking steps. A comprehensive molecular dynamic simulation (MDS) was conducted for each of the ligand-receptor complexes to figure out the values - root mean square deviation (RMSD) (Å), root mean square fluctuation (RMSF) (Å), H-bonds, Cα, solvent accessible surface area (SASA) (Å2), molecular surface area (MolSA) (Å2), Rg (nm), and polar surface area (PSA) (Å). Finally, computational programming and algorithms were used to interpret the dynamic simulation outputs into their graphical quantitative forms. RESULTS: ADMET and QSAR profiles revealed that the most active candidates from the library to be used were apigenin, isovitexin, piperolactam A, and quercetin as test ligands, whereas serpentine as the control. Based on the binding affinities of supramolecular docking and the parameters of molecular dynamic simulation, the strength of the test ligands can be classified as isovitexin > quercetin > piperolactam A > apigenin when complexed with the hACE2 receptor. Surprisingly, serpentine showed lower affinity (-8.6 kcal/mol) than that of isovitexin (-9.9 kcal/mol) and quercetin (-8.9 kcal/mol). The MDS analysis revealed all ligands except isovitexin having a value lower than 2.5 Ǻ. All the test ligands exhibited acceptable fluctuation ranges of RMSD (Å), RMSF (Å), H-bonds, Cα, SASA (Å2), MolSA (Å2), Rg (nm), and PSA (Å) values. CONCLUSION: Considering each of the parameters of molecular optimization, docking, and dynamic simulation interventions, all of the test ligands can be suggested as potential targeted drugs in blocking the hACE2 receptor.