In silico evaluation of the compounds of the ayurvedic drug, AYUSH-64, for the action against the SARS-CoV-2 main protease.

BACKGROUND: Outbreak of Corona Virus Disease in late 2019 (COVID-19) has become a pandemic global Public health emergency. Since there is no approved anti-viral drug or vaccine declared for the disease and investigating existing drugs against the COVID-19. OBJECTIVE: AYUSH-64 is an Ayurvedic formulation, developed and patented by Central Council of Research in Ayurvedic Sciences, India, has been in clinical use as anti-malarial, anti-inflammatory, anti-pyretic drug for few decades. Thus, the present study was undertaken to evaluate AYUSH-64 compounds available in this drug against Severe Acute Respiratory Syndrome-Corona Virus (SARS-CoV-2) Main Protease (Mpro; PDB ID: 6LU7) via in silico techniques. MATERIALS AND METHODS: Different molecular docking software's of Discovery studio and Auto Dock Vina were used for drugs from selected AYUSH-64 compounds against SARS-CoV-2. We also conducted 100 ns period of molecular dynamics simulations with Desmond and further MM/GBSA for the best complex of AYUSH-64 with Mpro of SARS-CoV-2. RESULTS: Among 36 compounds of four ingredients of AYUSH-64 screened, 35 observed to exhibits good binding energies than the published positive co-crystal compound of N3 pepetide. The best affinity and interactions of Akuammicine N-Oxide (from Alstonia scholaris) towards the Mpro with binding energy (AutoDock Vina) of -8.4 kcal/mol and Discovery studio of Libdock score of 147.92 kcal/mol. Further, molecular dynamics simulations with MM-GBSA were also performed for Mpro- Akuammicine N-Oxide docked complex to identify the stability, specific interaction between the enzyme and the ligand. Akuammicine N-Oxide is strongly formed h-bonds with crucial Mpro residues, Cys145, and His164. CONCLUSION: The results provide lead that, the presence of Mpro- Akuammicine N-Oxide with highest Mpro binding energy along with other 34 chemical compounds having similar activity as part of AYUSH-64 make it a suitable candidate for repurposing to management of COVID-19 by further validating through experimental, clinical studies.

A Comparative Review on Current and Future Drug Targets Against Bacteria & Malaria.

Long before the discovery of drugs like 'antibiotic and anti-parasitic drugs', the infectious diseases caused by pathogenic bacteria and parasites remain as one of the major causes of morbidity and mortality in developing and underdeveloped countries. The phenomenon by which the organism exerts resistance against two or more structurally unrelated drugs is called multidrug resistance (MDR) and its emergence has further complicated the treatment scenario of infectious diseases. Resistance towards the available set of treatment options and poor pipeline of novel drug development puts an alarming situation. A universal goal in the post-genomic era is to identify novel targets/drugs for various life-threatening diseases caused by such pathogens. This review is conceptualized in the backdrop of drug resistance in two major pathogens i.e. "Pseudomonas aeruginosa" and "Plasmodium falciparum". In this review, the available targets and key mechanisms of resistance of these pathogens have been discussed in detail. An attempt has also been made to analyze the common drug targets of bacteria and malaria parasite to overcome the current drug resistance scenario. The solution is also hypothesized in terms of a present pipeline of drugs and efforts made by scientific community.

Antiplasmodial potential of extracts from two species of genus Blumea.

CONTEXT: A number of Blumea (Asteraceae) species are being used in traditional Chinese and Indian folklore medicines to cure various diseases including cancer, fungal and bacterial infections. OBJECTIVE: To evaluate the in vitro antiplasmodial potential and cytotoxicity of various extracts and fractions of B. membranacea DC and B. eriantha DC and high performance liquid chromatography (HPLC) chemical fingerprinting of their crude extracts. MATERIALS AND METHODS: The aerial parts and roots of B. membranacea and B. eriantha were extracted with ethanol and the extracts were successively partitioned with n-hexane, ethyl acetate and n-butanol, which were later evaluated for their in vitro antiplasmodial activity against Plasmodium falciparum NF-54 and in vitro cytotoxicities against non-cancerous Vero cell line. HPLC chemical fingerprinting was performed on extracts of B. membranacea and B. eriantha. RESULTS: The n-hexane (MA1), ethyl acetate (MA2) fractions of aerial parts and n-butanol (MR3) fraction of roots of B. membranacea showed IC50 values of 17.4, 19.0 and 3.3 µg/mL respectively, while the n-hexane (EA1), ethyl acetate (EA2) fractions of aerial parts and ethyl acetate (ER2) fraction of roots of B. eriantha showed IC50 values of 25.0, 26.5 and 15.6 µg/mL, respectively, against P. falciparum NF-54. All these fractions were non-toxic to Vero cells. DISCUSSION AND CONCLUSION: Both B. membranacea and B. eriantha possesses a high degree of selective antiplasmodial activity (selectivity index up to >60) and hence, may find their use in antimalarial phytopharmaceuticals as well as in discovery of a safer and novel antimalarial lead.

Expression of CspE by a psychrotrophic bacterium Enterobacter ludwigii PAS1, isolated from Indian Himalayan soil and in silico protein modelling, prediction of conserved residues and active sites.

Proteome analysis of Enterobacter ludwigii PAS1 provide a powerful set of tool to study the cold shock proteins along with that combination of bioinformatics is useful for interpretation of comparative results from many species. There is a considerable interest in the use of psychrotrophic bacteria for nitrogen fixation, especially at hilly regions, thus better understanding of cold adaptation mechanisms too. The psychrotrophic E. ludwigii PAS1 grown at 30 and 4 °C, isolated from Himalaya soil was undertaken for proteomic responses during optimal and cold shock conditions. Comparative proteomic analyses using two-dimensional gel electrophoresis (2-DE) and MALDI-TOF/TOF MS revealed the presence of Cold shock protein E (CspE). Three-dimensional structure of CspE of E. ludwigii PAS1 divulge the presence of five antiparallel ß-sheets forming a ß-barrel structure with surface exposed aromatic and basic residues that were responsible for nucleic acid binding and also reveals the presence of highly conserved nucleic acid-binding motifs RNP1 and RNP2 in Csp family.

Novel antiplasmodial agents from Christia vespertilionis.

The roots, leaves and stems of Christia vespertilionis were separately and successively extracted with methanol and aqueous-methanol (1:4, v/v) and were evaluated in vitro for their antiplasmodial potential against Plasmodium falciparum NF-54. The aqueous-methanolic stem (AS) extract was the most active (IC50 7.5 microg/mL) followed by the methanolic leaf (ML) extract (IC50 32.0 microg/mL). The in vivo antimalarial activity of the combined plant extract of C. vespertilionis was also assessed in P. berghei infected mice, which showed 87.8% suppression of parasitaemia as compared with complete suppression by chloroquine on day 8. Finally, detailed chemical investigation of C. vespertilionis resulted in the isolation and characterization of fifteen compounds (1-15), of which two (1 and 4) are being reported for the first time from nature. The novel compound 1 possesses potent antiplasmodial activity (IC50 = 9.0 microg/mL).

Antiplasmodial activity of steroidal chalcones: evaluation of their effect on hemozoin synthesis and the new permeation pathway of Plasmodium falciparum-infected erythrocyte membrane.

Chalcone derivatives on an estradiol framework were evaluated for their ability to inhibit the growth and development of the malaria parasite Plasmodium falciparum. Out of twelve steroidal chalcones and one indanone derivative studied, three were found to have 50% growth inhibitory concentration less than 5µm and minimum inhibitory concentration for parasite development from ring to schizont stage as ≤20µm with best activity for gallic acid-based chalcone derivative 1 as 2.07 and 10µm, respectively. Two of the active derivatives 1 and 10 did not exhibit cytotoxicity against vero cells as evident by the good selectivity ratio. Study of structure-activity relationship indicated that increasing substitution in the benzoyl ring-enhanced antiplasmodial activity. Hemozoin synthesis of the parasite remained unaffected by these derivatives. These derivatives were also investigated for their effect on parasite-induced new permeation pathway in the erythrocyte membrane by sorbitol-induced hemolysis, and four derivatives 1, 2, 9, and 10 exhibited significant inhibition (>70%) at 20µm concentration. A positive correlation was also observed among the antiplasmodial activity and inhibition of new permeation pathway. These observations suggest that steroidal chalcones with selective activity for the parasite may be considered as antimalarial leads for further optimization and preclinical study.

Proteomics indicates modulation of tubulin polymerization by L-menthol inhibiting human epithelial colorectal adenocarcinoma cell proliferation.

Menthol is a naturally occurring cyclic monoterpene used in oral hygiene products, confectionary, pharmaceuticals, cosmetics, pesticides, and as a flavoring agent. In the present study, we analyzed the differentially expressing proteome in L-menthol-treated Caco-2 cell line as it was found to inhibit cell proliferation. Interestingly, free tubulin proteins were observed to be limited after menthol treatment. Semiquantitative RT-PCR with α-tubulin primers showed no change in the level of RNA expression in menthol-treated cell line. However, tubulin polymerization assay with menthol indicated a trend similar to taxol in promoting microtubule assembly. Further, physical counting of apoptotic nuclei and active caspase-3 assays confirmed onset of apoptosis though the rate was slower as compared with that of taxol treatment. This study is the first report of a monoterpene L-menthol modulating tubulin polymerization and apoptosis to inhibit cancer cell proliferation.

Antimicrobial potential of Glycyrrhiza glabra roots.

The present study was aimed to investigate antimicrobial potential of Glycyrrhiza glabra roots. Antimycobacterial activity of Glycyrrhiza glabra was found at 500 microg/mL concentration. Bioactivity guided phytochemical analysis identified glabridin as potentially active against both Mycobacterium tuberculosis H(37)Ra and H(37)Rv strains at 29.16 microg/mL concentration. It exhibited antimicrobial activity against both Gram-positive and Gram-negative bacteria. Our results indicate potential use of licorice as antitubercular agent through systemic experiments and sophisticated anti-TB assay.

Synthesis of 1-(3',4',5'-trimethoxy) phenyl naphtho[2,1b]furan as a novel anticancer agent.

3',4',5'-Trimethoxy benzoyl-naphthalene 2-O-acetic acid (5) underwent base catalysed intramolecular condensation to yield exclusively 1-(3',4',5'-trimethoxy) phenyl naphtho[2,1-b]furan 8. The cyclised product 8 has been characterised by spectroscopy. The product 8 showed significant anticancer activity against human cancer cell lines COLO320DM (colon), CaCO2 (colon) and WRL68 (liver) at 0.7, 0.65 and 0.50 microg/ml concentrations, respectively, in the in vitro MTT assay.