Showing papers in "Combinatorial Chemistry & High Throughput Screening in 2021"

Molecular Docking and Virtual Screening based prediction of drugs for COVID-19.

Abstract: Aims To predict potential drugs for COVID-19 by using molecular docking for virtual screening of drugs approved for other clinical applications. Background SARS-CoV-2 is the betacoronavirus responsible for the COVID-19 pandemic. It was listed as a potential global health threat by the WHO due to high mortality, high basic reproduction number, and lack of clinically approved drugs and vaccines. The genome of the virus responsible for COVID-19 has been sequenced. In addition, the three-dimensional structure of the main protease has been determined experimentally. Objective To identify potential drugs that can be repurposed for treatment of COVID-19 by using molecular docking based virtual screening of all approved drugs. Methods A list of drugs approved for clinical use was obtained from the SuperDRUG2 database. The structure of the target in the apo form, as well as structures of several target-ligand complexes, were obtained from RCSB PDB. The structure of SARS-CoV-2 Mpro determined from X-ray diffraction data was used as the target. Data regarding drugs in clinical trials for COVID-19 was obtained from clinicaltrials.org. Input for molecular docking based virtual screening was prepared by using Obabel and customized python, bash, and awk scripts. Molecular docking calculations were carried out with Vina and SMINA, and the docked conformations were analyzed and visualized with PLIP, Pymol, and Rasmol. Results Among the drugs that are being tested in clinical trials for COVID-19, Danoprevir and Darunavir were predicted to have the highest binding affinity for the Main protease (Mpro) target of SARS-CoV-2. Saquinavir and Beclabuvir were identified as the best novel candidates for COVID-19 therapy by using Virtual Screening of drugs approved for other clinical indications. Conclusion Protease inhibitors approved for treatment of other viral diseases have the potential to be repurposed for treatment of COVID-19.

Discovery of Potent SARS-CoV-2 Inhibitors from Approved Antiviral Drugs via Docking and Virtual Screening

Abstract: BACKGROUND: Corona Virus Disease 2019 (COVID-19) pandemic threatens patients, societies and healthcare systems around the world. There is an emergent need to search for possible medications. OBJECTIVE: This article intends to use virtual screening and molecular docking methods to find potential inhibitors that can respond to COVID-19 from existing drugs. METHODS: To tack part in the current research investigation to define a potential target drug that may protect the world from emerged pandemic corona disease, we have carried out a virtual screening study by of 129 approved drugs that their metabolic characteristics, dosages used, potential efficacy and side effects are clear as they have been approved for treating existing infections. Especially 12 drugs against chronic hepatitis B virus, 37 against chronic hepatitis C virus, 37 against human immunodeficiency virus, 14 anti-herpesvirus, 11 anti- influenza, and 18 others drugs currently on the market were considered for this study. Then these drugs were evaluated using virtual screening and molecular docking studies in the active site of the (SARS-CoV-2) main protease (6lu7). Once the efficacy of the drug is determined, it can be approved for of their in vitro and in vivo activity against the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), that could be interesting for rapid clinical treatment of patients. These drugs were ranked for potential effectiveness against SARS-CoV-2 and those with high molecular docking scores are proposed as novel candidates for repurposing. The N3 inhibitor co-crystallized with the protease (6lu7) and the anti-HIV protease inhibitor Lopinavir were used as standards for comparison. RESULTS: The results suggest the effectiveness of Beclabuvir, Nilotinib, Tirilazad, Trametinib and Glecaprevir as potent drugs against SARS-CoV-2 since they tightly bind to its main protease. CONCLUSION: These promising drugs could inhibit the replication of the virus; hence, we suggest the repurposing of these compounds for thetreatment of COVID-19. No toxicity measurements are required for these drugs since they were previously tested prior to their approval by the FDA. However, the assessment of these potential inhibitors as clinical drugs involves further in vivo tests for these drugs.

MHD flow of a Newtonian fluid in symmetric channel with ABC fractional model containing hybrid nanoparticles.

Abstract: INTRODUCTION The nanofluid is novelty of nanotechnology to overcome the difficulties of heat transfer in several manufacturing and engineering areas. Fractional calculus has many applications in nearly all fields of science and engineering which comprises electrochemistry, dispersion and viscoelasticity. OBJECTIVES This paper focused on the heat transfer of hybrid nanofluid in two vertical parallel plates and presented a comparison between fractional operators. METHODS The fractional viscous fluid model is considered with physical initial and boundary conditions for the movement occurrences. The analytical solutions were obtained via Laplace transform method for the concentration, temperature and velocity fields. After that we presented a comparison between Atangana-Baleanu (ABC), Caputo (C) and Caputo-Fabrizio (CF) fractional operators. RESULTS The comparison of different base fluids (Water, kerosene, Engine Oil) is discussed graphically for temperature and velocity. It is resulted that due to high thermal conductivity in water, temperature and velocity are high. While engine oil has maximum viscosity than water and kerosene, so temperature and velocity are very low. Due to the thermal conductivity improving with the enrichment of hybrid nanoparticles, so the Temperature is increased and since viscosity increased, so the velocity is reduced. CONCLUSION Atangana-Baleanu (ABC) fractional operator gives better memory effect of concentration, temperature and velocity fields than Caputo (C) and Caputo-Fabrizio (CF). Temperature and velocity of water with hybridized nanoparticles is high in comparison with kerosene and engine oil.

Lead Finding from Selected Flavonoids with Antiviral (SARS-CoV-2) Potentials against COVID-19: An in-silico Evaluation.

Abstract: BACKGROUND COVID-19 is a pandemic respiratory contagious viral (SARS-CoV-2) disease associated with high morbidity and mortality worldwide. Currently, there are no effective preventive or treatment strategies for COVID-19 and it has been declared as a global health emergency by WHO. In silico molecular docking studies can be useful to predict the binding affinity between the phytocompound and the target protein and play a vital role in finding an inhibitor through structure-based drug design. OBJECTIVE In this aspect, our objective was to screen essential flavonoids against possible protein targets such as SARS-CoV-2 spike glycoprotein receptor binding domain (RBD-S) and host Angiotensin Converting Enzyme-2 protease domain (PD-ACE-2) using in silico molecular docking studies. METHODS Approximately 49 flavonoids were identified and were evaluated for their drug-likeness based on Lipinski rule, bioactivity scores, antiviral and toxicity profiles using SwissADME, Molinspiration, PASS and GUSAR online tools. The flavonoids that passed Lipinski rule were subjected to in silico analysis through molecular docking on RBD-S and PD-ACE-2 using Molegro Virtual Docker v6.0. RESULTS The bioactive flavonoids that showed NIL violations and were found in compliance with Lipinski rule were selected for docking studies. In silico analysis reported that biochanin A and silymarin bind significantly at the active sites of RBD-S and PD-ACE-2 with a MolDock score of -78.41and -121.28 kcal/mol respectively. Bioactivity scores, antiviral potential and toxicity profiles were predicted for the top interacting phytocompounds and substantial relevant data was reported. CONCLUSION The current outcomes created a new paradigm for understanding biochanin A and silymarin bioflavonoids as potent inhibitors of RBD-S and PD-ACE-2 targets respectively. Further work can be extended to confirm their therapeutic potential for COVID-19.

Tinocordiside from Tinospora cordifolia (Giloy) May Curb SARS-CoV-2 Contagion by Disrupting the Electrostatic Interactions between Host ACE2 and Viral S-Protein Receptor Binding Domain.

Abstract: Background SARS-CoV-2 has been shown to bind the host cell ACE2 receptor through its spike protein receptor binding domain (RBD), required for its entry into the host cells. Objective We have screened phytocompounds from a medicinal herb, Tinospora cordifolia, for their capacities to interrupt the viral RBD and host ACE2 interactions. Method We employed molecular docking to screen phytocompounds in T. cordifolia against the ACE2-RBD complex, performed molecular dynamics (MD) simulation, and estimated the electrostatic component of binding free energy. Results 'Tinocordiside' docked very well at the center of the interface of ACE2-RBD complex, and was found to be well stabilized during MD simulation. Tinocordiside incorporation significantly decreased electrostatic component of binding free energies of ACE2-RBD complex (23.5 and 17.10 kcal/mol in the trajectories without or with the ligand, respectively). As the basal rate constant of protein association is in the order of 5, (105 to 106 M-1 S-1 ), there might be no big conformational change or loop reorganization, but involves only local conformational change typically observed in diffusion-controlled association. Taken together, the increase in global flexibility of the complex, clearly indicates the start of unbinding process of the complex. Conclusion It indicates that such an interruption of electrostatic interactions between the RBD and ACE2, and the increase in global flexibility of the complex, would weaken or block SARS-CoV-2 entry and its subsequent infectivity. We postulate that natural phytochemicals like Tinocordiside could be the viable options for controlling SARS-CoV-2 contagion and its entry into host cells.

The Screening of Phytochemicals Against NS5 Polymerase to Treat Zika Virus Infection: Integrated Computational Based Approach

Abstract: Background The recent Zika virus (ZIKV) outbreak provides a spur for new, efficient, and safe anti-Zika Virus agents. RNA-dependent RNA polymerase (RdRp) is critical amongst the seven non-structural proteins for viral replication and is considered an attractive drug target. Methods In this study, a molecular docking approach was used to rationally screen the library of 5000 phytochemicals to find inhibitors against NS5 RdRp. LigX tool was used to analyze the 2D plots of receptor-ligand interactions. The top-ranked compounds were then subjected to in-silico pharmacokinetic study. Results The compounds, namely Polydatin, Dihydrogenistin, Liquiritin, Rhapontin, and Cichoriin, successfully bind inside the pocket of NS5 RdRp. Polydatin was the leading phytochemical that showed high docking score of -18.71 (kcal/mol) and bonding interaction at the active site of NS5 RdRp. They were subjected to analysis for drug-like properties that further reinforced their validation and showed that they could attach with the receptor more than SOFOSBUVIR control drugs. MD simulation of the top two complexes was performed, and the simulated complexes showed stability, and ligands were kept within the bonding pocket. Conclusion The study might facilitate the development of a natural and cost-effective drug against ZIKV. Further validation, however, is necessary to confirm its drug effectiveness and its biocompatibility.

Potential Leads from Liquorice against SARS-CoV-2 Main Protease using Molecular Docking Simulation Studies.

Abstract: Aim and objective At present, the world is facing a global pandemic threat of SARSCoV- 2 or COVID-19 and to date, there are no clinically approved vaccines or antiviral drugs available for the treatment of coronavirus infections. Studies conducted in China recommended the use of liquorice (Glycyrrhiza species), an integral medicinal herb of traditional Chinese medicine, in the deactivation of COVID-19. Therefore, the present investigation was undertaken to identify the leads from the liquorice plant against COVID-19 using molecular docking simulation studies. Materials and methods A set of reported bioactive compounds of liquorice were investigated for COVID-19 main protease (Mpro) inhibitory potential. The study was conducted on Autodock vina software using COVID-19 Mpro as a target protein having PDB ID: 6LU7. Results Out of the total 20 docked compounds, only six compounds showed the best affinity towards the protein target, which included glycyrrhizic acid, isoliquiritin apioside, glyasperin A, liquiritin, 1-methoxyphaseollidin and hedysarimcoumestan B. From the overall observation, glycyrrhizic acid followed by isoliquiritin apioside demonstrated the best affinity towards Mpro representing the binding energy of -8.6 and -7.9 Kcal/mol, respectively. Nevertheless, the other four compounds were also quite comparable with the later one. Conclusion From the present investigation, we conclude that the compounds having oxane ring and chromenone ring substituted with hydroxyl 3-methylbut-2-enyl group could be the best alternative for the development of new leads from liquorice plant against COVID-19.

Molecular Mechanisms of Thymoquinone as Anticancer Agent.

Abstract: Thymoquinone (TQ), the bioactive constituent of Nigella Sativa seeds is a well-known natural compound for the management of several types of cancers. The anti-cancer properties of thymoquinone are thought to be operated via intervening with various oncogenic pathways including cell cycle arrest, prevention of inflammation and oxidative stress, induction of invasion, metastasis, inhibition of angiogenesis, and apoptosis. As well as up-regulation and down-regulation of specific tumor suppressor genes and tumor promoting genes, respectively. Proliferation of various tumor cells is inhibited by TQ via induction of cell cycle arrest, disruption of the microtubule organization, and down regulating cell survival protein expression. TQ induces G1 phase cell cycle arrest in human breast cancer, colon cancer and osteosarcoma cells through inhibiting the activation of cyclin E or cyclin D and up-regulating p27and p21 a cyclin dependent kinase (Cdk) inhibitor. TQ concentration is a significant factor in targeting a particular cell cycle phase. While high concentration of TQ induced G2 phase arrest in human breast cancer (MCF-7) cells, low concentration causes S phase arrest. This review article provides mechanistic insights into the anti-cancer properties of thymoquinone.

Diagnosis of Alzheimer's Disease Based on Deeply-Fused Nets.

Abstract: Aim and objective Fast and accurate diagnosis of Alzheimer's disease is very important for the care and further treatment of patients. Along with the development of deep learning, impressive progress has also been made in the automatic diagnosis of AD. Most existing studies on automatic diagnosis are concerned with a single base network, whose accuracy for disease diagnosis still needs to be improved. This study was undertaken to propose a method to improve the accuracy of automatic diagnosis of AD. Materials and methods MRI image data from the Alzheimer's Disease Neuroimaging Initiative were used to train a deep learning model to achieve computer-aided diagnosis of Alzheimer's disease. The data consisted of 138 with AD, 280 with mild cognitive impairment, and 138 normal controls. Here, a new deeply-fused net is proposed, which combines several deep convolutional neural networks, thereby avoiding the error of a single base network and increasing the classification accuracy and generalization capacity. Results Experiments show that when differentiating between patients with AD, mild cognitive impairment, and normal controls on a subset of the ADNI database without data leakage, the new architecture improves the accuracy by about 4 percentage points as compared to a single standard base network. Conclusion This new approach exhibits better performance, but there is still much to be done before its clinical application. In the future, greater research effort will be devoted to improving the performance of the deeply-fused net.

The Antiviral and Antimalarial Drug Repurposing in Quest of Chemotherapeutics to Combat COVID-19 Utilizing Structure-Based Molecular Docking.

Abstract: Background The novel coronavirus disease (COVID-19) is caused by a new strain (SARS-CoV-2) erupted in 2019. Nowadays, it is a great threat that claims uncountable lives worldwide. There is no specific chemotherapeutics developed yet to combat COVID-19. Therefore, scientists have been devoted in the quest of the medicine that can cure COVID- 19. Objective Existing antivirals such as ASC09/ritonavir, lopinavir/ritonavir with or without umifenovir in combination with antimalarial chloroquine or hydroxychloroquine have been repurposed to fight the current coronavirus epidemic. But exact biochemical mechanisms of these drugs towards COVID-19 have not been discovered to date. Method In-silico molecular docking can predict the mode of binding to sort out the existing chemotherapeutics having a potential affinity towards inhibition of the COVID-19 target. An attempt has been made in the present work to carry out docking analyses of 34 drugs including antivirals and antimalarials to explain explicitly the mode of interactions of these ligands towards the COVID-19protease target. Results 13 compounds having good binding affinity have been predicted towards protease binding inhibition of COVID-19. Conclusion Our in silico docking results have been confirmed by current reports from clinical settings through the citation of suitable experimental in vitro data available in the published literature.

Systematic Evaluation of the Mechanisms of Mulberry Leaf (Morus alba Linne) Acting on Diabetes Based on Network Pharmacology and Molecular Docking

Abstract: Background Diabetes mellitus is one of the most common endocrine metabolic disorder- related diseases. The application of herbal medicine to control glucose levels and improve insulin action might be a useful approach in the treatment of diabetes. Mulberry leaves (ML) have been reported to exert important activities of anti-diabetic. Objective In this work, we aimed to explore the multi-targets and multi-pathways regulatory molecular mechanism of Mulberry leaves (ML, Morus alba Linne) acting on diabetes. Methods Identification of active compounds of Mulberry leaves using Traditional Chinese Medicine Systems Pharmacology (TCMSP) database was carried out. Bioactive components were screened by FAF-Drugs4 website (Free ADME-Tox Filtering Tool). The targets of bioactive components were predicted from SwissTargetPrediction website, and the diabetes related targets were screened from GeneCards database. The common targets of ML and diabetes were used for Gene Ontology (GO) and pathway enrichment analysis. The visualization networks were constructed by Cytoscape 3.7.1 software. The biological networks were constructed to analyze the mechanisms as follows: (1) compound-target network; (2) common target-compound network; (3) common targets protein interaction network; (4) compound-diabetes protein-protein interactions (ppi) network; (5) target-pathway network; and (6) compound-target-pathway network. At last, the prediction results of network pharmacology were verified by molecular docking method. Results 17 active components were obtained by TCMSP database and FAF-Drugs4 website. 51 potential targets (11 common targets and 40 associated indirect targets) were obtained and used to build the PPI network by the String database. Furthermore, the potential targets were used for GO and pathway enrichment analysis. Eight key active compounds (quercetin, Iristectorigenin A, 4- Prenylresveratrol, Moracin H, Moracin C, Isoramanone, Moracin E and Moracin D) and 8 key targets (AKT1, IGF1R, EIF2AK3, PPARG, AGTR1, PPARA, PTPN1 and PIK3R1) were obtained to play major roles in Mulberry leaf acting on diabetes. And the signal pathways involved in the mechanisms mainly include AMPK signaling pathway, PI3K-Akt signaling pathway, mTOR signaling pathway, insulin signaling pathway and insulin resistance. The molecular docking results show that the 8 key active compounds have good affinity with the key target of AKT1, and the 5 key targets (IGF1R, EIF2AK3, PPARG, PPARA and PTPN1) have better affinity than AKT1 with the key compound of quercetin. Conclusion Based on network pharmacology and molecular docking, this study provided an important systematic and visualized basis for further understanding of the synergy mechanism of ML acting on diabetes.

Flavonoids and other Non-alkaloidal Constituents of Genus Erythrina: Phytochemical Review.

Abstract: BACKGROUND Genus Erythrina belongs to family Fabaceae, which is widely distributed in tropical and subtropical areas. It has been used in both traditional herbal medicines and pharmacological applications. Original research articles and publications on the overview of alkaloids related to this genus are available, but a supportive systematic review account which highlighted phytochemical aspects of other types of secondary metabolites is currently insufficient. OBJECTIVE With the utilization of data and information from SCI-Finder, Google Scholar, the Web of Science, Scopus, Science Direct, PubMed, Chemical Abstracts, ACS journals, Springer, Taylor Francis, Bentham Science and IOP Science, the reliable material sources of this systematic review paper were obtained from the literature published from the 1980s to now. CONCLUSION A vast amount of data showed that the non-alkaloidal secondary metabolites were obtained from genus Erythrina with various classes of chemical structures. Herein, approximately five hundred constituents were isolated, comprising flavonoids, terpenoids, saponins, phytosterols, phenols, arylbenzofurans, coumarins, alcohols, ceramides, mono-sugars and fatty acid derivatives. In agreement with the previous phytochemical reports on the plants of the family Fabaceae, flavonoids reached a high amount in the plants of genus Erythrina. Numerous biological activity investigations such as anti-bacteria, anti-cancer, anti-virus using isolated compounds from Erythrina species suggested that secondary metabolites of Erythrina plants are now becoming the promising agents for drug developments.

Herbal Medicine: Clinical Perspective and Regulatory Status.

Abstract: Herbal medicines play an important role in treating various ailments due to their potentially high therapeutic values and acceptability by patients with different health complications. The practice of herbal medicine involves the use of a part of a plant, the entire plant, or a selective isolated phytoconstituent. The search for new drugs during the scientific era revived the interest in the discovery of herbal drugs from different natural resources. The present modern healthcare system involves the utilization of drugs and 50% of them are of natural origin. In recent years, there had been an upsurge in the interest for search of novel herbal drugs by the pharmaceutical industry. However, the discovery of such new novel phytomedicines involves various challenges in the identification of active constituents; their characterization, pharmacological activity, toxicity/adverse effects, drug interactions, and, most importantly, their regulatory requirements. The present review is mainly focused on the history of herbal medicine, current clinical perspective, and pharmaceutical and regulatory challenges facing herbal drugs. Moreover, problems encountered in drug discovery from herbal resources and their possible solutions have been delineated.

Effect of visnagin on altered steroidogenesis and spermatogenesis, and testicular injury induced by the heavy metal lead

Abstract: Background Lead (Pb) is an environmental pollutant causing serious health problems, including impairment of reproduction. Visnagin (VIS) is a furanochromone with promising antioxidant and anti-inflammatory effects; however, its protective efficacy against Pb toxicity has not been investigated. Objective This study evaluated the protective effect of VIS on Pb reproductive toxicity, impaired steroidogenesis and spermatogenesis, oxidative stress and inflammation. Methods Rats received VIS (30 or 60 mg/kg) and 50 mg/kg lead acetate for 3 weeks and blood and testes samples were collected. Results Pb intoxication impaired the pituitary-testicular axis (PTA) manifested by the decreased serum levels of gonadotropins and testosterone. Pb decreased sperm count, motility and viability, increased sperm abnormalities, and downregulated the steroidogenesis markers StAR, CYP17A1, 3β-HSD and 17β-HSD in the testis of rats. VIS significantly increased serum gonadotropins and testosterone, alleviated sperm parameters and upregulated steroidogenesis. In addition, VIS decreased pro-inflammatory cytokines, testicular lipid peroxidation and DNA fragmentation, downregulated Bax, and enhanced antioxidants and Bcl-2. Conclusion These results demonstrate the protective effect of VIS against Pb reproductive toxicity in rats. VIS improved serum gonadotropins and testosterone, enhanced steroidogenesis and spermatogenesis, and attenuated oxidative injury, inflammation and apoptosis. Therefore, VIS is a promising candidate for the protection against Pb-induced reproduction impairment.

An Insight Into the Anxiolytic Effects of Lignans (Phyllanthin and Hypophyllanthin) and Tannin (Corilagin) Rich Extracts of Phyllanthus amarus : An In-Silico and In-vivo approaches.

Abstract: The extracts and the compounds isolated from Phyllanthus amarus Schumm and Thonn (Family: Euphorbiaceae) have shown a wide spectrum of pharmacological activities including antiviral, antibacterial, antiplasmodial, antimalarial, antimicrobial, anticancer, antidiabetic, hypolipidemic, antioxidant, hepatoprotective, nephroprotective and diurectic properties. BACKGROUND This investigation was aimed at exploring the anxiolytic potential of Phyllanthus amarus standardized extracts and predict probable role of marker phyto constitutents. OBJECTIVE AND METHODS Three standardized extracts of Phyllanthus amarus plant viz. standardized aqueous extract of Phyllanthus amarus whole plant (PAAE), standardized methanolic extract of P. amarus leaf (PAME) and the standardized hydro-methanolic extract of P. amarus leaf (PAHME) were tested in the classical animal models of anxiety: Elevated plus-maze model and Light & Dark Exploration test. RESULTS The lower doses of the tannin rich extract (PAHME) of the P. amarus possess significant anxiolytic activity compared to lignin rich (PAME) and aqueous extracts (PAAE), while at a higher dose (400mg/kg) the results of all three extracts appears to be potentially sedative. While the molecular docking studies support these probable anxiolytic, the sedative effects of the Phyllanthus amarus extracts could be due to the interaction of tannins and lignans with the GABAbenzodiazepine receptor complex. CONCLUSION The results of the present study indicate that the tannin-rich extract of the P. amarus may have potential clinical applications in the management of anxiety. It can be further studied for optimum dosage to be used as a future of anti-anxiety drug development or as a standardized Phytomedicine.

Novel Drug Delivery System for Curcumin: Implementation to Improve Therapeutic Efficacy against Neurological Disorders.

Abstract: Background Curcumin, a hydrophobic polyphenolic compound present in Curcuma longa Linn. (Turmeric), has been used to improve various neurodegenerative conditions, including Amyotrophic lateral sclerosis, Multiple Sclerosis, Parkinson's disease, Prion disease, stroke, anxiety, depression, and ageing. However, the blood-brain barrier (BBB) impedes the delivery of curcumin to the brain, as a result, limits its therapeutic potential. Objective/aim This review summarises the recent advances towards the therapeutic efficacy of curcumin along with various novel strategies to overcome its poor bioavailability across the blood-brain barrier. Methods The collection of data for the compilation of this review work was searched in PubMed Scopus, Google Scholar, and Science Direct. Result Various approaches have been opted to expedite the delivery of curcumin across the blood-brain barrier, including liposomes, micelles, polymeric nanoparticles, exosomes, dual targeting Nanoparticles etc. Conclusion: The review also summarises the numerous toxicological studies and the role of curcumin in CNS disorders.

Exploring the Potential Mechanism of Shufeng Jiedu Capsule for Treating COVID-19 by Comprehensive Network Pharmacological Approaches and Molecular Docking Validation.

Abstract: OBJECTIVE Shufeng Jiedu capsule (SFJDC) is a well-known Chinese patent drug that is recommended as a basic prescription and applied widely in the clinical treatment of COVID-19. However, the exact molecular mechanism of SFJDC remains unclear. The present study aims to determine the potential pharmacological mechanisms of SFJDC in the treatment of COVID-19 based on network pharmacology. METHODS The network pharmacology-based strategy includes collection and analysis of active compounds and target genes, network construction, identification of key compounds and hub target genes, KEGG and GO enrichment, recognition and analysis of main modules, as well as molecule docking. RESULTS A total of 214 active chemical compounds and 339 target genes of SFJDC were collected. Of note, 5 key compounds (β -sitosterol, luteolin, kaempferol, quercetin, and stigmasterol) and 10 hub target genes (TP53, AKT1, NCOA1, EGFR, PRKCA, ANXA1, CTNNB1, NCOA2, RELA and FOS) were identified based on network analysis. The hub target genes mainly enriched in pathways including MAPK signaling pathway, PI3K-Akt signaling pathway and cAMP signaling pathway, which could be the underlying pharmacological mechanisms of SFJDC for treating COVID-19. Moreover, the key compounds had high binding activity with three typical target proteins including ACE2, 2OFZ, and 1SSK. CONCLUSION By network pharmacology analysis, SFJDC was found to effectively improve immune function and reduce inflammatory responses based on its key compounds, hub target genes, and the relevant pathways. These findings may provide valuable evidence for explaining how SFJDC exerting the therapeutic effects on COVID-19, providing a holistic view for further clinical application.

A Systems Biology Approach for miRNA-mRNA Expression Patterns Analysis in Rheumatoid Arthritis

Abstract: Objective Considering the molecular complexity and heterogeneity of rheumatoid arthritis (RA), the identification of novel molecular contributors involved in RA initiation and progression using systems biology approaches will open up potential therapeutic strategies. The bioinformatics method allows the detection of associated miRNA-mRNA as both therapeutic and prognostic targets for RA. Methods This research used a system biology approach based on a systematic re-analysis of the RA-related microarray datasets in the NCBI Gene Expression Omnibus (GEO) database to find out deregulated miRNAs. We then studied the deregulated miRNA-mRNA using Enrichr and Molecular Signatures Database (MSigDB) to identify novel RA-related markers followed by an overview of miRNA-mRNA interaction networks and RA-related pathways. Results This research mainly focused on mRNA and miRNA interactions in all tissues and blood/serum associated with RA to obtain a comprehensive knowledge of RA. Recent systems biology approach analyzed seven independent studies and presented important RA-related deregulated miRNAs (miR-145-5p, miR-146a-5p, miR-155-5p, miR-15a-5p, miR-29c-3p, miR- 103a-3p, miR-125a-5p, miR-125b-5p, miR-218); upregulation of miR-125b is shown in the study (GSE71600). While the findings of the Enrichr showed cytokine and vitamin D receptor pathways and inflammatory pathways. Further analysis revealed a negative correlation between the vitamin D receptor (VDR) and miR-125b in RA-associated gene expression. Conclusion Since vitamin D is capable of regulating the immune homeostasis and decreasing the autoimmune process through its receptor (VDR), it is regarded as a potential target for RA. According to the results obtained, a comparative correlation between negative expression of the vitamin D receptor (VDR) and miR-125b was suggested in RA. The increasing miR-125b expression would reduce the VitD uptake through its receptor.

The Cosmetic Potential of The Medicinal Halophyte Tamarix Gallica L. (Tamaricaceae) Growing in The Eastern Part of Algeria: Photoprotective and Antioxidant Activities.

Abstract: AIM AND OBJECTIVE Currently, the use of ingredients from natural sources has gained great attention in the cosmetic field, especially for the development of new photoprotective formulations. Therefore, the present study aimed to evaluate the cosmetic potential of the crude methanol extract and the ethyl acetate fraction of the medicinal halophyte Tamarix gallica L. (Tg) growing in the area of Tebessa in the eastern part of Algeria, by assessing their phenolic and flavonoid contents, photoprotective and antioxidant activities. METHODS The research approach consisted of determining phenolic and flavonoid contents of aerial parts via Folin-Ciocalteu and aluminum chloride methods, respectively. The antioxidant activity was measured through two in vitro methods, DPPH radical scavenging activity and total antioxidant capacity test (TAC). The in vitro photoprotective effect was evaluated according to the parameter SPF (Sun Protection Factor) by using the UV spectroscopic method in the UV-B region (290-320 nm). RESULTS The methanol extract (Tg-MeOH) and ethyl acetate (Tg-EtOAc) fraction showed good antioxidant activity with IC50 values of 14.05±0.66, 27.58±1.98 μg/mL respectively in the DPPH test. Furthermore, both extracts displayed strong total antioxidant capacity (287.01±7.85, 246.7±1.12 mg AAE/g, respectively) in the TAC test. Both extracts exhibited high photoprotective activity, with sun protection factor (SPF) values 37.03±0.22 and 36.08±0.03. The antioxidant and photoprotective activities of these extracts were probably related to polyphenols content (190.27±0.74 mg AGE /g and 121.77±1.29 mg AGE /g, respectively) and flavonoids (78.75±0.06 mg QE /g and 58.67±1.19mg/g). CONCLUSION Our findings show that extracts of Tamarix gallica L. could be a promising source to be mixed as a natural sunscreen and antioxidant agents into photoprotective cosmetic formulations.

Curcumin-containing Silver Nanoparticles Prevent Carbon Tetrachloride- induced Hepatotoxicity in Mice.

Abstract: Background Hepatotoxicity remains an important clinical challenge. Hepatotoxicity observed in response to toxins and hazardous chemicals may be alleviated by delivery of the curcumin in silver nanoparticles (AgNPs-curcumin). In this study, we examined the impact of AgNPs-curcumin in a mouse model of carbon tetrachloride (CCl4)-induced hepatic injury. Methods Male C57BL/6 mice were divided into three groups (n=8 per group). Mice in group 1 were treated with vehicle control alone, while mice in Group 2 received a single intraperitoneal injection of 1 ml/kg CCl4 in liquid paraffin (1:1 v/v). Mice in group 3 were treated with 2.5 mg/kg AgNPs-curcumin twice per week for three weeks after the CCl4 challenge. Results Administration of CCL4 resulted in oxidative dysregulation, including significant reductions in reduced glutathione and concomitant elevations in the level of malondialdehyde (MDA). CCL4 challenge also resulted in elevated levels of serum aspartate transaminase (AST) and alanine transaminase (ALT); these findings were associated with the destruction of hepatic tissues. Treatment with AgNPs-curcumin prevented oxidative imbalance, hepatic dysfunction, and tissue destruction. A comet assay revealed that CCl4 challenge resulted in significant DNA damage as documented by a 70% increase in nuclear DNA tail-length; treatment with AgNPs-curcumin inhibited the CCL4-mediated increase in nuclear DNA tail-length by 34%. Conclusion Administration of AgNPs-curcumin resulted in significant antioxidant activity in vivo. This agent has the potential to prevent the hepatic tissue destruction and DNA damage that results from direct exposure to CCL4.

Screening of Significant Biomarkers Related to Prognosis of Cervical Cancer and Functional Study Based on lncRNA-associated ceRNA Regulatory Network.

Abstract: Background Cervical cancer (CESC), which threatens the health of women, has a very high recurrence rate. Purposes This study aimed to identify the signature long non-coding RNAs (lncRNAs) associated with the prognosis of CESC and predict the prognostic survival rate with the clinical risk factors. Methods The CESC gene expression profiling data were downloaded from TCGA database and NCBI Gene Expression Omnibus. Afterwards, the differentially expressed RNAs (DERs) were screened using limma package of R software. R package "survival" was then used to screen the signature lncRNAs associated with independently recurrence prognosis, and a nomogram recurrence rate model based on these signature lncRNAs was constructed to predict the 3-year and 5-year survival probability of CESC. Fianlly, a competing endogenous RNAs (ceRNA) regulatory network was proposed to study the functions of these genes. Results We obtained 305 DERs significantly associated with prognosis. Afterwards, a risk score (RS) prediction model was established using the screened 5 signature lncRNAs associated with independently recurrence prognosis (DLEU1, LINC01119, RBPMS-AS1,RAD21-AS1and LINC00323). Subsequently, a nomogram recurrence rate model, proposed with Pathologic N and RS model status, was found to have good prediction ability for CESC. In ceRNA regulatory network,LINC00323 and DLEU1were hub nodes which targeted more miRNAs and mRNAs. After that, 15 GO terms and 3 KEGG pathways were associated with recurrence prognosis, and showed that the targeted genes PTK2, NRP1, PRKAA1and HMGCS1 may influence the prognosis of CESC. Conclusion The signature lncRNAs can help improve our understanding of the development and recurrence of CESC and the nomogram recurrence rate model can be applied to predict the survival rate of CESC patients in clinical practice.

A Potential MRI Agent and an Anticancer Drug Encapsulated within CPMV Virus-Like Particles.

Abstract: Background Virus nanoparticles have been extensively studied over the past decades for theranostics applications. Viruses are well-characterized, naturally occurring nanoparticles that can be produced in high quantity with a high degree of similarity in both structure and composition. Objectives The plant virus cowpea mosaic virus (CPMV) has been innovatively used as a nanoscaffold. Utilization of the internal cavity of empty virus-like particles (VLPs) for the inclusion of therapeutics within the capsid has opened many opportunities in drug delivery and imaging applications. Methods The encapsidation of magnetic materials and anticancer drugs was achieved. SuperscriptCPMV denotes molecules attached to the external surface of CPMV and CPMVSubscript denotes molecules within the interior of the capsid. Results Here, the generation of novel VLPs incorporating iron-platinum nanoparticles TCPMVFePt and cisplatin (Cis) (TCPMVCis) is reported. TCPMVCis have a cytotoxic IC50 of TCPMVCis on both A549 and MDA-MB-231 cell lines of 1.8 μM and 3.9 μM respectively after 72 hours of incubation. The TCPMVFePt were prepared as potential MRI contrast agents. Conclusions Cisplatin loaded VLP (TCPMVCis) is shown to enhance cisplatin cytotoxicity in cancer cell lines, and its potency increased 2.3-folds.

Moxifloxacin Hydrochloride-Loaded Eudragit® RL 100 and Kollidon® SR Based Nanoparticles: Formulation, In vitro Characterization and Cytotoxicity

Abstract: BACKGROUND Considering the low ocular bioavailability of conventional formulations used for ocular bacterial infection treatment, there is a need to design efficient novel drug delivery systems that may enhance precorneal retention time and corneal permeability. AIM AND OBJECTIVE The current research focuses on developing nanosized and non-toxic Eudragit® RL 100 and Kollidon® SR nanoparticles loaded with moxifloxacin hydrochloride (MOX) for its prolonged release to be promising for effective ocular delivery. METHODS In this study, MOX incorporation was carried out by spray drying method aiming ocular delivery. In vitro characteristics were evaluated in detail with different methods. RESULTS MOX was successfully incorporated into Eudragit® RL 100 and Kollidon® SR polymeric nanoparticles by a spray-drying process. Particle size, zeta potential, entrapment efficiency, particle morphology, thermal, FTIR, NMR analyses and MOX quantification using HPLC method were carried out to evaluate the nanoparticles prepared. MOX loaded nanoparticles demonstrated nanosized and spherical shape while in vitro release studies demonstrated modified-release pattern, which followed the Korsmeyer-Peppas kinetic model. Following the successful incorporation of MOX into the nanoparticles, the formulation (MOX: Eudragit® RL 100, 1:5) (ERL-MOX 2) was selected for further studies because of its better characteristics like cationic zeta potential, smaller particle size, narrow size distribution and more uniform prolonged release pattern. Moreover, ERLMOX 2 formulation remained stable for 3 months and demonstrated higher cell viability values for MOX. CONCLUSION In vitro characterization analyses showed that non-toxic, nano-sized and cationic ERL-MOX 2 formulation has the potential of enhancing ocular bioavailability.

Ultrasound-promoted Green Synthesis of pyrido[2,1-a]isoquinoline Derivatives and Studies on their Antioxidant Activity

Abstract: Aims & Objective: An efficient procedure for the synthesis of pyrido[2,1-a]isoquinoline derivatives in excellent yields was investigated using catalyst-free multicomponent reaction of phthaladehyde, methylamine, activated acetylenic compounds, alkyl bromides and triphenylphosphine in water under ultrasonic irradiation at room temperature. In addition, Diels- Alder reactions of pyrido[2,1-a]isoquinoline derivatives with activated acetylenic compounds under ultrasonic irradiation are investigated in two procedures. The advantages of this procedure compared to report methods are short time of reaction, high yields of product, easy separation of product, clean mixture of reaction and green media for performing reaction. In addition, because of having isoquinoline core in synthesized compounds, in this research antioxidant activity of some synthesized compounds was studied. MATERIALS AND METHODS To a stirred mixture of phthalaldehyde 1 (2 mmol) and methylamine 2 (2 mmol) in water (3 mL) under ultrasonic irradiation was added to activated acetylenic compounds 4 after 20 min. Alkyl bromide 3 and triphenylphosphine 5 react in another pot in water (3 mL) under ultrasonic irradiation for 15 min. After this time, this mixture was added to the first pot. After completion of the reaction, the solid residue was separated by filtration and washed with Et2O to afforded pure title compound 6. RESULTS In this work, generation of pyrido[2,1-a]isoquinoline derivatives 6 are performed using phthalaldehyde 1, methylamine 2, α-halo substituted carbonyls 3, activated acetylenic compounds 4 and triphenylphosphine 5 in water under ultrasonic irradiation condition at room temperature in excellent yield at short time. CONCLUSION In summary, multicomponent reaction of phthaladehyde, methylamine, activated acetylenic compounds, alkyl bromides and triphenylphosphine in water under ultrasonic irradiation at room temperature produced pyrido[2,1-a]isoquinoline derivatives in excellent yields. Also, Diels-Alder reaction of pyrido[2,1-a]isoquinoline derivatives with activated acetylenic compounds and triphenylphosphine under ultrasonic irradiation is investigated in two procedures. Also, the antioxidant activities of 6a, 6c, 6g and 6i were evaluated by DPPH radical scavenging and ferric reducing power analyzes. The compounds 6a exhibit excellent DPPH radical scavenging activity and FRAP compared to synthetic antioxidants BHT and TBHQ. The chief benefits of our method are high atom economy, green reaction conditions, higher yield, shorter reaction times, and easy work-up, which agree with some principles of green chemistry.

Lung Nodule Detection using Convolutional Neural Networks with Transfer Learning on CT Images

Abstract: Aim and objective Lung nodule detection is critical in improving the five-year survival rate and reducing mortality for patients with lung cancer. Numerous methods based on convolutional neural networks (CNNs) have been proposed for lung nodule detection in computed tomography (CT) images. With the collaborative development of computer hardware technology, the detection accuracy and efficiency can still be improved. Materials and methods In this study, an automatic lung nodule detection method using CNNs with transfer learning is presented. We first compare three of the state-of-the-art convolutional neural network (CNN) models, namely, VGG16, VGG19 and ResNet50, to determine the most suitable model for lung nodule detection. We then utilize two different training strategies, namely, freezing layers and fine-tuning, to illustrate the effectiveness of transfer learning. Furthermore, the hyper-parameters of the CNN model such as optimizer, batch size and epoch are optimized. Results Evaluated on the Lung Nodule Analysis 2016 (LUNA16) challenge, promising results with an accuracy of 96.86%, a precision of 91.10%, a sensitivity of 90.78%, a specificity of 98.13%, and an AUC of 99.37% are achieved. Conclusion Compared with other works, state-of-the-art specificity is obtained, which demonstrates that the proposed method is effective and applicable to lung nodule detection.

Recent trends in QSAR in Modelling of Drug-Protein and Protein-Protein Interactions.

Abstract: The unprecedented growth in the area of QSAR has completely changed the landscape of drug discovery. QSAR techniques quantitatively correlate the associations between chemical structure alterations and respective changes in biological activity, thereby playing a major role in improving the potency, efficacy and selectivity of the lead compounds in drug design. In this review, authors have summarized the role of QSAR in drug discovery, especially with respect to lead optimization and drug-receptor interactions. The recent trends in the usage of 3D-QSAR to understand protein-Protein Interactions (PPIs) have been explored. Specifically, the latest advances in the concepts of chemical Space (CS) and chemography have been examined in detail. Also, the authors have tried to present the current limitations and challenges in this field. The authors agree with the prevalent view that the models must be systematically validated both internally as well as externally to strengthen the hit rates in the experiments. It is important to apply the 'in cerebro-in silico' approach that entails choosing the method specific to the target-ligand system.

Mechanistic Insights to the Binding of Antibody CR3022 Against RBD from SARS-CoV and HCoV-19/SARS-CoV-2: A Computational Study.

Abstract: Aims & Objective: Corona Virus Disease 2019 (COVID-19) caused by the human coronavirus 2019 (HCoV-19, also known as SARS-CoV-2) infection is currently in a global outbreak. COVID-19 has posed a huge threat to public health and economic stability worldwide. CR3022, a human monoclonal neutralizing antibody isolated from a Severe Acute Respiratory Syndrome (SARS) recovery patient, was confirmed to be able to bind the S protein of HCoV-19 with a certain degree of neutralizing activity. Crystal structural information indicated that CR3022 could bind to the epitope on the receptor binding domain (RBD) of HCoV-19, whose epitope consists of 28 amino acids, and 24 of them are conserved in SARS-CoV of SARS. However, the crystal structure is only a static conformation at a certain moment in time, and it cannot provide dynamic details of the interaction between antigen and antibody. Methods: In this study, molecular dynamics (MD) simulation combined with MM/PBSA and CAS methods were performed to investigate the binding mechanism of binding of CR3022 against SARS-CoV-RBD and HCoV-19-RBD in order to determine their holographic dynamic information. Results: It was found that the CR3022-SARS-CoV-RBD complex was more stable during 100ns MD run than that of the CR3022-HCoV19-RBD system. There were common conservative amino acids on the s2 sheet of RBD, including Tyr369, Phe377, Lys378, Tyr380, Gly381, Lys386, Leu390 and others. These conservative amino acids play significant roles in the binding process of CR3022 antibody against SARS-CoV-RBD and HCoV-19-RBD. It was also found that the binding mode of CR3022 to its native target SARS-CoV-RBD is more comprehensive and uniform. Moreover, the s2 sheet residue Thr385 and non-s2 sheet residues Arg408 and Asp428 of the CR3022- SARS-CoV-RBD system were found to be crucial for their binding affinities, thus forming a special conformational epitope. However, these key amino acids are not present in the CR3022-HCoV-19-RBD system. The binding mode of CR3022 and HCoV-19-RBD is similar to that of SARS-CoV-RBD, but the deficiency of crucial hydrogen-bonds and salt-bridges. Therefore, the binding of CR3022 and HCoV19-RBD only draws on the partial mode of the binding of CR3022 and SARS-CoV-RBD, so there is a loss of affinity. Conclusion: Thus, in order to better fight the epidemic of COVID-19 with the CR3022 antibody, this antibody needs to further improve the neutralization efficiency of HCoV-19 through mutation of it's CDR region.

Andrographolide Mitigates Unfolded Protein Response Pathway and Apoptosis Involved in Chikungunya Virus Infection

Abstract: Background Chikungunya virus (CHIKV) is an arthropod-borne RNA virus which induces host Endoplasmic Reticulum (ER) stress by accumulating unfolded or misfolded proteins. ER stress activates the unfolded protein response (UPR) pathway to enable proper protein folding and maintain cellular homeostasis. There is no approved drug or vaccine available for CHIKV treatment, therefore, a pharmacological countermeasure is warranted for preventing CHIKV infection. Objective With a view to find a treatment modality for chikungunya infection, "andrographolide", a plant-derived diterpenoid with reported antiviral, anti-inflammatory and immunomodulatory effects, was used to investigate its role in chikungunya induced unfolded protein stress and apoptosis. Methods Cells and supernatant collected on andrographolide and VER-155008, a GRP78 inhibitor, treatment in CHIKV infected and mock-infected THP-1 cells were tested for differential expression of UPR pathway proteins including GRP78, PERK, EIF-2α, IRE-1α, XBP-1 and ATF6. Furthermore, the inflammasome and apoptosis pathway proteins, i.e., caspase-1, caspase-3 and PARP, were tested by immunoblotting, and cytokines, i.e., IL-1β, IL-6 and IFN-γ were tested by ELISA. Results Andrographolide treatment in CHIKV infected THP-1 cells significantly reduced IRE1α and downstream spliced XBP1 protein expression. Furthermore, CHIKV induced apoptosis and viral protein expression were also reduced on andrographolide treatment. A comparative analysis of andrographolide versus VER-155008, confirmed that andrographolide surpasses the effects of VER-155008 in suppressing the CHIKV induced ER stress. Conclusion The study, therefore, confirms that andrographolide is a potential remedy for chikungunya infection and suppresses CHIKV induced ER stress and apoptosis.

Anti-Ulcerogenic and Cytoprotective Effects of Saharian (Sidr) Honey from Algeria

Abstract: AIM AND OBJECTIVE This study aimed at investigating the gastro-protective effects of Algerian Sahara (Sidr) honey from Apis mellifera intermissa against HCl/Ethanol-induced gastric ulcers in rats. MATERIALS AND METHODS Total phenolic content, antioxidant activity and phenolic compounds were determined. Then, three groups of rats (control, HCl/ Ethanol-induced ulcer, and orally administered honey) were used for the determination of gastro-protective effect of Sidr honey. RESULTS Total phenolic content, total flavonoid content, and DPPH activity of the honey sample were determined as 47.35±3.35 mg GAE/ 100 g, 2.13±0.17 mg QE/ 100 g, and 229.24±0.02 mg/mL, respectively. Oral pretreatment of rats with honey (1.2 g/Kg body weight orally at an interval of 2 days) protected gastric mucosa against HCl/Ethanol-induced damage by decreasing ulcer score, the volume and acidity of gastric juice and increasing pH. CONCLUSION These results were confirmed by the histological assessment, which demonstrated a significant gastro-protective activity of Saharian (Sidr) honey against HCl/Ethanol-induced stomach ulcer. Plasma tumor necrosis factor-α, IL-6 and PGE2 were also measured. Sahara honey significantly decreased the plasma TNF-α, PGE2, and IL-6 concentrations.

Protective Role of Morus nigra Leaf Extracts against Murine Infection with Eimeria papillata.

Abstract: BACKGROUND Eimeriosis is a parasitic intestinal infection that affects the poultry industry; it is responsible for economic losses on a global scale. OBJECTIVE This study investigated the protective role of Morus nigra leaf extracts (ME) against Eimeria papillata infection in mice. METHODS C57Bl/6 mice were divided into six groups. The first group was gavaged daily with 100 μL 0.9% NaCl. The second group was treated daily by oral gavage with 100 μL M. nigra leaf extracts (ME) (200 mg/kg), while the third, fourth, fifth, and sixth groups were orally infected with 1000 E. papillata oocysts. The last three groups were daily treated for 5 days with 200, 400, and 800 mg/kg of ME, respectively. Samples of jejunum were obtained for examining the histopathological changes as well as changes in the nitric oxide and catalase levels. RESULTS Infrared spectroscopy of ME showed the presence of several expected active classes of phytochemical compounds. ME was able to reduce the E. papillata oocysts in mice feces by about 80% and decrease the infection-induced jejunal histopathological injuries. This was quantified using the histological injury score. In addition, ME significantly recovered the changes in nitric oxide and catalase levels. CONCLUSION Our findings showed that the M. nigra extract has an antioxidant activity which protects against murine eimeriosis. Further studies are required to determine the exact active compounds in ME and their mode of action.