The emergence of the Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) has resulted in a long pandemic, with numerous cases and victims worldwide and enormous consequences on social and economic life. Although vaccinations have proceeded and provide a valuable shield against the virus, the approved drugs are limited and it is crucial that further ways to combat infection are developed, that can also act against potential mutations. The main protease (Mpro) of the virus is an appealing target for the development of inhibitors, due to its importance in the viral life cycle and its high conservation among different coronaviruses. Several compounds have shown inhibitory potential against Mpro, both in silico and in vitro, with few of them also having entered clinical trials. These candidates include: known drugs that have been repurposed, molecules specifically designed based on the natural substrate of the protease or on structural moieties that have shown high binding affinity to the protease active site, as well as naturally derived compounds, either isolated or in plant extracts. The aim of this work is to collectively present the results of research regarding Mpro inhibitors to date, focusing on the function of the compounds founded by in silico simulations and further explored by in vitro and in vivo assays. Creating an extended portfolio of promising compounds that may block viral replication by inhibiting Mpro and by understanding involved structure–activity relationships, could provide a basis for the development of effective solutions against SARS-CoV-2 and future related outbreaks. 

https://doi.org/10.1016/j.csbj.2022.03.009

Inhibition of the main protease of SARS-CoV-2 (Mpro) by repurposing/designing drug-like substances and utilizing nature’s toolbox of bioactive compounds

In this study, we examined aqueous extracts of the edible mushrooms Pleurotus ostreatus (oyster mushroom) and Lentinula edodes (shiitake mushroom). Proteome analysis was conducted using LC-Triple TOF-MS and showed the expression of 753 proteins by Pleurotus ostreatus, and 432 proteins by Lentinula edodes. Bioactive peptides: Rab GDP dissociation inhibitor, superoxide dismutase, thioredoxin reductase, serine proteinase and lectin, were identified in both mushrooms. The extracts also included promising bioactive compounds including phenolics, flavonoids, vitamins and amino acids. The extracts showed promising antiviral activities, with a selectivity index (SI) of 4.5 for Pleurotus ostreatus against adenovirus (Ad7), and a slight activity for Lentinula edodes against herpes simplex-II (HSV-2). The extracts were not cytotoxic to normal human peripheral blood mononuclear cells (PBMCs). On the contrary, they showed moderate cytotoxicity against various cancer cell lines. Additionally, antioxidant activity was assessed using DPPH radical scavenging, ABTS radical cation scavenging and ORAC assays. The two extracts showed potential antioxidant activities, with the maximum activity seen for Pleurotus ostreatus (IC50 µg/mL) = 39.46 ± 1.27 for DPPH; 11.22 ± 1.81 for ABTS; and 21.40 ± 2.20 for ORAC assays. This study encourages the use of these mushrooms in medicine in the light of their low cytotoxicity on normal PBMCs vis a vis their antiviral, antitumor and antioxidant capabilities.

https://www.mdpi.com/1420-3049/26/15/4623/pdf

Proteome Analysis and In Vitro Antiviral, Anticancer and Antioxidant Capacities of the Aqueous Extracts of Lentinula edodes and Pleurotus ostreatus Edible Mushrooms

In this study, we investigated aqueous extracts of three edible mushrooms: Agaricus bisporus (white button mushroom), Pleurotus columbinus (oyster mushroom), and Pleurotus sajor-caju (grey oyster mushroom). The extracts were biochemically characterized for total carbohydrate, phenolic, flavonoid, vitamin, and protein contents besides amino acid analysis. Triple TOF proteome analysis showed 30.1% similarity between proteomes of the two Pleurotus spp. All three extracts showed promising antiviral activities. While Pleurotus columbinus extract showed potent activity against adenovirus (Ad7, selectivity index (SI) = 4.2), Agaricus bisporus showed strong activity against herpes simplex II (HSV-2; SI = 3.7). The extracts showed low cytotoxicity against normal human peripheral blood mononuclear cells (PBMCs) and moderate cytotoxicity against prostate (PC3, DU-145); colorectal (Colo-205); cecum carcinoma (LS-513); liver carcinoma (HepG2); cervical cancer (HeLa); breast adenocarcinoma (MDA-MB-231 and MCF-7) as well as leukemia (CCRF-CEM); acute monocytic leukemia (THP1); acute promyelocytic leukemia (NB4); and lymphoma (U937) cell lines. Antioxidant activity was evaluated using 2,2-diphenyl-1-picryl-hydrazyl-hydrate (DPPH) radical scavenging, 2,2'-Azinobis-(3-Ethylbenzthiazolin-6-Sulfonic Acid) ABTS radical cation scavenging, and oxygen radical absorbance capacity (ORAC) assays. The three extracts showed potential antioxidant activities with the maximum activity recorded for Pleurotus columbinus (IC50 µg/mL) = 35.13 ± 3.27 for DPPH, 13.97 ± 4.91 for ABTS, and 29.42 ± 3.21 for ORAC assays.

Antiviral, Cytotoxic, and Antioxidant Activities of Three Edible Agaricomycetes Mushrooms: Pleurotus columbinus, Pleurotus sajor-caju, and Agaricus bisporus.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has infected billions and has killed millions to date. Studies are being carried out to find therapeutic molecules that can potentially inhibit the replication of SARS-CoV-2. 3-chymotrypsin-like protease (3CL pro) involved in the polyprotein cleavage process is believed to be the key target for viral replication, and hence is an attractive target for the discovery of antiviral molecules. In the present study, we aimed to identify natural phytocompounds from Bridelia retusa as potential inhibitors of SARS-CoV-2 3CL pro (PDB ID: 6M2N) using in silico techniques. Molecular docking studies conducted with three different tools in triplicates revealed that ellagic acid (BR6) and (+)-sesamin (BR13) has better binding affinity than the co-crystal inhibitor “3WL” of 6M2N. BR6 and BR13 were found to have a high LD50 value with good bioavailability. 3WL, BR6, and BR13 bind to the same active binding site and interacted with the HIS41-CYS145 catalytic dyad including other crucial amino acids. Molecular dynamics simulation studies revealed stability of protein–ligand complexes as evidenced from root-mean-square deviations, root-mean-square fluctuations (RMSF), protein secondary structure elements, ligand-RMSF, protein–ligand contacts, ligand torsions, and ligand properties. BR6 (−22.3064 kcal/mol) and BR13 (−19.1274 kcal/mol) showed a low binding free energy value. The Bayesian statistical model revealed BR6 and BR13 as better protease inhibitors than 3WL. Moreover, BR6 and BR13 had already been reported to elicit antiviral activities. Therefore, we conclude that ellagic acid and (+)-sesamin as natural antiviral phytocompounds with inhibitory potential against SARS-CoV-2 3CL pro. 

/pdf/antiviral-phytocompounds-ellagic-acid-and-sesamin-of-27ddqt1g.pdf

Antiviral phytocompounds “ellagic acid” and “(+)-sesamin” of Bridelia retusa identified as potential inhibitors of SARS-CoV-2 3CL pro using extensive molecular docking, molecular dynamics simulation studies, binding free energy calculations, and bioactivity prediction

Abstract The outbreak of COVID-19 has become a global crisis, and brought severe disruptions to societies and economies. Until now, effective therapeutics against COVID-19 are in high demand. Along with our improved understanding of the structure, function, and pathogenic process of SARS-CoV-2, many small molecules with potential anti-COVID-19 effects have been developed. So far, several antiviral strategies were explored. Besides directly inhibition of viral proteins such as RdRp and M pro , interference of host enzymes including ACE2 and proteases, and blocking relevant immunoregulatory pathways represented by JAK/STAT, BTK, NF-κB, and NLRP3 pathways, are regarded feasible in drug development. The development of small molecules to treat COVID-19 has been achieved by several strategies, including computer-aided lead compound design and screening, natural product discovery, drug repurposing, and combination therapy. Several small molecules representative by remdesivir and paxlovid have been proved or authorized emergency use in many countries. And many candidates have entered clinical-trial stage. Nevertheless, due to the epidemiological features and variability issues of SARS-CoV-2, it is necessary to continue exploring novel strategies against COVID-19. This review discusses the current findings in the development of small molecules for COVID-19 treatment. Moreover, their detailed mechanism of action, chemical structures, and preclinical and clinical efficacies are discussed. 

/pdf/small-molecules-in-the-treatment-of-covid-19-313d7e1y.pdf

Small molecules in the treatment of COVID-19

This study aims to identify and isolate the secondary metabolites of Zingiber officinale using GC-MS, preparative TLC, and LC-MS/MS methods, to evaluate the inhibitory potency on SARS-CoV-2 3 chymotrypsin-like protease enzyme, as well as to study the molecular interaction and stability by using docking and molecular dynamics simulations. GC-MS analysis suggested for the isolation of terpenoids compounds as major compounds on methanol extract of pseudostems and rhizomes. Isolation and LC-MS/MS analysis identified 5-hydro-7, 8, 2′-trimethoxyflavanone (9), (E)-hexadecyl-ferulate (1), isocyperol (2), N-isobutyl-(2E,4E)-octadecadienamide (3), and nootkatone (4) from the rhizome extract, as well as from the leaves extract with the absence of 9. Three known steroid compounds, i.e., spinasterone (7), spinasterol (8), and 24-methylcholesta-7-en-3β-on (6), were further identified from the pseudostem extract. Molecular docking showed that steroids compounds 7, 8, and 6 have lower predictive binding energies (MMGBSA) than other metabolites with binding energy of −87.91, −78.11, and −68.80 kcal/mole, respectively. Further characterization on the single isolated compound by NMR showed that 6 was identified and possessed 75% inhibitory activity on SARS-CoV-2 3CL protease enzyme that was slightly different with the positive control GC376 (77%). MD simulations showed the complex stability with compound 6 during 100 ns simulation time.

GC-MS, LC-MS/MS, Docking and Molecular Dynamics Approaches to Identify Potential SARS-CoV-2 3-Chymotrypsin-Like Protease Inhibitors from Zingiber officinale Roscoe.

Introduction: Human immunodeficiency virus type-1 (HIV-1) that causes acquired immunodeficiency syndrome (AIDS) has become a worldwide health problem today. There are approximately 30 anti-HIV-1 drugs that have been used in the treatment of AIDS. However, effective anti HIV-1 agents with less side affect and high inhibition potency are still in demand. Objective: The objective of this study was to identify the potential compounds from Zingiberaceae plants that might be active as anti-HIV-1 by molecular docking. Materials and Methods: Molecular docking simulation was performed by using AutoDock 4.2 on Linux operation system. Docking protocol was validated by using root mean square deviation (RMSD) value using redocking and cross-docking methods. The reported metabolites from Zingiberaceae plants were docked on HIV-1 protease, integrase, and reverse transcriptase protein enzymes. Results: The docking result showed that the genera of Zingiber, Etlingera, Alpinia, Hedychium, and Boesenbergia have potential metabolites that inhibit HIV protease, integrase, and reverse transcriptase enzymes by possessing lower docking energy than native ligand of amprenavir, raltegravir, and nevirapine. Among the metabolites, noralpindenoside B and alpindenoside A from Alpinia densespicata inhibited protease enzymes with the lowest docking energy of -18.02 and -17.90 kcal/mol, respectively. Meanwhile, panduratin E from Boesenbergia pandurata Roxb. and 5α,8α-epidioxyergosta-6,22-dien-3β-ol from Etlingera elatior showed the lowest docking energy on integrase protein with docking energy of -11.97 and -11.41 kcal/mol, respectively. Pahangensin A from Alpinia pahangensis Ridley showed the lowest docking energy on reverse transcriptase enzyme with docking energy of -13.76 kcal/mol. Conclusion: The docking molecular study has identified the possible potential compounds from Zingiberaceae plants that might be used for anti-HIV-1 treatment. So, this study suggested further isolation and purification of the predicted compounds.

Docking study on anti-HIV-1 activity of secondary metabolites from Zingiberaceae plants

Research on gingers and their traditional uses by three different indigenous ethnic groups at Lore Lindu National Park, Central Sulawesi, Indonesia was carried out from February to June 2018. The objectives of the research was to gain information about the diversity of the family Zingiberaceae and its traditional uses by the Topo Baria, Toi Toro Muma and To Kaili Ledo people. Key informants were traditional healers (sando), traditional leaders (adat), community leaders, village leaders, religion leaders, government officers and crafts-people. The interviews were recorded using audio recorders and notebooks. Samples of plants were collected and photographed while recording the information. Response was obtained by "Snowball technique". A total of 24 species of Zingiberaceae were used of which 19 were determined to species level. Eight species were collected from natural forest, while 14 were recorded from agricultural habitat. Four of the species were endemic to Sulawesi (Alpinia eremochlamys, A. rubricaulis, Etlingera acanthodes and E. flexuosa). Fourteen species were not native to Sulawesi but widely cultivated in the region. The information about the uses by the Topo Baria was not adequate whereas the contrary the Toi Toro Muma and To Kaili Ledo used several species for various daily purposes, such as medicine, spice, cosmetics, ornamentals, or to be eat freshly.

Diversity of Zingiberaceae and traditional uses by three indigenous groups at Lore Lindu National Park, Central Sulawesi, Indonesia

The research on structure and floristic composition of vegetation of  the Lore Lindu National Park has been conducted  from  October to  Desember 2010. The objectives of the research was to study the vegetation potency are included species richness, structure and composition. The Research was located at three locations namely : Bora (elevation  400- 800 m asl), Nokilalaki (elevation 1300-1800 m asl) and Rorekautimbu  (elevation  2100 – 2600 m asl).  The research was used survey methods through establisment of transect with 20 m in wide.  and in line transect was made nested plot continuously with the size of 20 X 20 m for the observation of trees (dbh> 20 cm), 10 x 10 m for poles, 5 X 5 m and 2 x 2 m to observe the saplings and understorey layer. The result showed that the plant species richness (incl. tree, pole, sapling and seedling and understory plant) in Nokilalaki was higher than  Bora and Rorekautimbu. The diversity index  of Nokilalaki was also higher than Bora and Rorekautimbu. The species composition and structure was indicated the significantly different, where the location I (Bora) was dominated by Dracaena arborea and Tamarindus indica , besides Nokilalaki was dominated by Lithocarpus elegans and Castanopsis accuminatisima (both Fagaceae).  On the other side Rorekautimbu was dominated by Podocarpaceae family such as: Phyllocladus hypophyllus and Dracrycarpus imbricatus . All of research sites studied were very rich with plants are have potency to develop as raw material for  medicine such as Begonia sp, Tasmania piperita and Galbulimima belgraveana . Besides that it was also can be developed as ornamental plant such as: Agalmailla sp (Gesneriaceae), Rhododendrons sp, Vaccinium sp  (both Ericaceae) and several species of pitcher plants  ( Nepenthes spp) and soon

/pdf/struktur-dan-komposisi-vegetasi-pada-3-zona-elevasi-yang-rggundz09u.pdf

Struktur Dan Komposisi Vegetasi Pada 3 Zona Elevasi Yang Berbeda Di Taman Nasional Lore Lindu Sulawesi Tengah Indonesia

. Pitopang R, Umrah, Harso W, Nurainas, Zubair MS. 2020. Some botanical aspects and antifungal activity of Etlingera flexuosa (Zingiberaceae) from Central Sulawesi, Indonesia. Biodiversitas 21: 3547-3553. Etlingera flexuosa is a species of Etlingera endemic to the island of Sulawesi and its natural distribution is restricted to Central and South Sulawesi, where it has been utilized for different purposes. Despite the limited knowledge in the aspects of botany and its antimicrobial activities, the use of plants as a source of alternative solutions to health problems is on the rise. The objectives of this study were to obtain some information about the several botanical aspects of E. flexuosa and its antifungal activity. This research was conducted from March to December 2019 and samples were collected from the montane forest of Lore Lindu National Park (LLNP) near Sedoa Village, Lore Utara Sub-district, Poso District, Indonesia. The identification of plant specimens and extractions was carried out at the Laboratory of Plant Biosystematics, Tadulako University, Palu, Indonesia. The antifungal activity was tested using agar diffusion methods. The results showed that E. flexuosa is a perennial herb naturally distributed in Sulawesi island. It usually grows in the pristine submontane and montane forests, sometimes in light and open condition or on the slope of natural disturbed forest at the altitude of 1500 -1700 m a.s.l. The forest is dominated by Fagaceae family, of which E. flexuosa has been utilized extensively by local community of Topo Baria ethnic for various purposes such as flavor enhancer in food, vegetable, traditional medicine, and as roofing materials. It contains some secondary metabolites such as flavonoids, tannins, saponins, terpenoids, alkaloids and steroids, and also shows antioxidant activity. Conclusively, the extract of E. flexuosa could be used as inhibiting agent for the growth of Candida albicans yeast.

/pdf/some-botanical-aspects-of-etlingera-flexuosa-zingiberaceae-1ogphb1boy.pdf

Ramadanil Pitopang

Papers

GC-MS, LC-MS/MS, Docking and Molecular Dynamics Approaches to Identify Potential SARS-CoV-2 3-Chymotrypsin-Like Protease Inhibitors from Zingiber officinale Roscoe.

Docking study on anti-HIV-1 activity of secondary metabolites from Zingiberaceae plants

Diversity of Zingiberaceae and traditional uses by three indigenous groups at Lore Lindu National Park, Central Sulawesi, Indonesia

Struktur Dan Komposisi Vegetasi Pada 3 Zona Elevasi Yang Berbeda Di Taman Nasional Lore Lindu Sulawesi Tengah Indonesia

Some botanical aspects of Etlingera flexuosa (Zingiberaceae) from Central Sulawesi (Indonesia) and its antifungal activity