Molecular Docking study of Severe Acute Respiratory Syndrome Coronavirus 2 Spike Glycoprotein with Celastroid Triterpenoid Inhibitors

Bagchi et al.: Screening of Severe Acute Respiratory Syndrome Coronavirus 2 inhibitors Severe acute respiratory syndrome coronavirus 2 poses a huge threat to humans. The beta genus Severe acute respiratory syndrome coronavirus 2 has four structural proteins: Spike, envelope, membrane and nucleocapsid protein. Among them, spike plays an important role in the host cell attachment and fusion. The S1 subunit of the spike is responsible for bonding to the host and hence is the most crucial target for finding appropriate inhibitors. Molecular docking calculations at the receptor binding domain of S1 subunit have been carried out with twenty celastroid triterpenoids and found that they have very good binding energies. The interactions of these compounds with important amino acid residues were also thoroughly investigated. The docking poses were further validated by the farPPI web server.

In silico-based studies on phytochemicals from native Indian plants as potential inhibitors of SARS-CoV-2

This study aims to analyze the AntiCovid effect of Phytocompounds extracted from Native Indian Plant species by computational methods such as Molecular Docking. Through this study keeping the Indian Heritage alive we characterized the ability of these phytochemicals as inhibiting agents of the Main Protease enzyme of this Virus. The lack of any effective treatment and the reoccurrence of cases despite Vaccination necessitates the quick provision of anti-SARS-CoV-2 drugs. Natural substances are getting a lot of attention for SARS-CoV-2 therapy as they have proven antimicrobial activities and are a key source for numerous antiviral drugs. Despite the fact that this virus has several identified target receptors, Main Protease (Mpro) is crucial for viral replication. In this study, 26 phytochemicals from 10 native Indian plant species were studied. Our docking studies demonstrated that compounds Quercetin, Withaferin A, Sominone, and Nimbin were likely to be more favorable than the natural inhibitor N3, with binding energies of-8.42, -9.21, -9.95, and -8.88 kcal/mol, respectively. These four candidate natural compounds were further examined for their bioavailability scores through ADMET analysis to prove the safety of these compounds as well as their drug likeliness. Through the results it was indicated that these natural phytochemicals have a significant potential of inhibiting the SARS-CoV-2 Mpro enzyme and might be utilized to treat SARS-CoV-2 and manage public health, subject to in vitro validation in the future.

Study in-silico oleanane triterpenoids in Aquilaria spp. as a COVID-19 antiviral

Covid-19, a disease characterized by Severe Acute Respiratory Syndrome, is caused by Coronavirus-2 (SARS-CoV-2). This virus causes tissue damage and a decrease in the respiratory system. Agarwood (Aquilaria spp) is a plant that has various pharmacological activities, including relieving respiratory diseases. One of the several secondary metabolites reported in Aquilaria spp. is oleanane triterpenoids, suspected of having antiviral activity. This research was aimed to determine the potential of oleanane triterpenoids from Agarwood as a covid-19 antiviral by in silico study. The research methods were molecular docking, prediction of Lipinski rules of five, and prediction of ADME. As a receptor, main protease (Mpro) Covid-19 was used. The four oleanane triterpenoid compounds in Agarwood demonstrated a higher affinity for the main protease covid-19 (G 11-oxo-beta-amyrin = -9.8 kcal/mol, G hederagenin-an = -9.6 kcal/mol, G 3beta-acetoxyfriedelane = -9.4 kcal/mol, G ursolic acid = -9.5 kcal/mol) than Lopinavir (G = -6.2 kcal/mol) and Remdesivir (G = -7.2 kcal/mol). The major amino acids involved in ligand and receptor interactions are methionine 49 and 165, proline 168, glutamine 189, arginine 188, and threonine 25. According to the prediction of Lipinski's rule of five and ADME, hederageninan is potential for development as oral medicine.

Study In-Silico Oleanane Triterpenoids in Aquilaria spp. as a Covid-19 Antiviral

Covid-19, a disease characterized by Severe Acute Respiratory Syndrome, is caused by Coronavirus-2 (SARS-CoV-2). This virus causes tissue damage and a decrease in the respiratory system. Agarwood (Aquilaria spp) is a plant that has various pharmacological activities, including relieving respiratory diseases. One of the several secondary metabolites reported in Aquilaria spp. is oleanane triterpenoids, suspected of having antiviral activity. This research was aimed to determine the potential of oleanane triterpenoids from Agarwood as a covid-19 antiviral by in silico study. The research methods were molecular docking, prediction of Lipinski rules of five, and prediction of ADME. As a receptor, main protease (Mpro) Covid-19 was used. The four oleanane triterpenoid compounds in Agarwood demonstrated a higher affinity for the main protease covid-19 (ΔG 11-oxo-β-amyrin = -9.8 kcal/mol, ΔG hederagenin-an = -9.6 kcal/mol, ΔG 3β-acetoxyfriedelane = -9.4 kcal/mol, ΔG ursolic acid = -9.5 kcal/mol) than Lopinavir (ΔG = -6.2 kcal/mol) and Remdesivir (ΔG = -7.2 kcal/mol). The major amino acids involved in ligand and receptor interactions are methionine 49 and 165, proline 168, glutamine 189, arginine 188, and threonine 25. According to the prediction of Lipinski's rule of five and ADME, hederageninan is potential for development as oral medicine.

Ganoderma lucidum: Unutilized natural medicine and promising future solution to emerging diseases in Africa.

Ganoderma lucidum is a well-known medicinal mushroom that has been used for the prevention and treatment of different ailments to enhance longevity and health specifically in China, Japan, and Korea. It was known as "God's herb" in ancient China as it was believed to prolong life, enhance the youthful spirit and sustain/preserve vitality. G. lucidum is seldom collected from nature and is substantially cultivated on wood logs and sawdust in plastic bags or bottles to meet the international market demand. Both in vitro and in vivo studies on the copious metabolic activities of G. lucidum have been carried out. Varied groups of chemical compounds including triterpenoids, polysaccharides, proteins, amino acids, nucleosides, alkaloids, steroids, lactones, lectins, fatty acids, and enzymes with potent pharmacological activities have been isolated from the mycelia and fruiting bodies of G. lucidum. Several researchers have reported the abundance and diversification of its biological actions triggered by these chemical compounds. Triterpenoids and polysaccharides of G. lucidum have been reported to possess cytotoxic, hepatoprotective, antihypertensive, hypocholesterolemic, antihistaminic effects, antioxidant, antimicrobial, anti-inflammatory, hypoglycemic antiallergic, neuroprotective, antitumor, immunomodulatory and antiangiogenic activities. Various formulations have been developed, patented, and utilized as nutraceuticals, cosmeceuticals, and pharmaceuticals from G. lucidum extracts and active compounds. Thus, this review presents current updates on emerging infectious diseases and highlights the scope, dynamics, and advances in infectious disease management with a particular focus on Ganoderma lucidum, an unutilized natural medicine as a promising future solution to emerging diseases in Africa. However, details such as the chemical compound and mode of action of each bioactive against different emerging diseases were not discussed in this study.

Lucidenic acid A inhibits the binding of hACE2 receptor with spike protein to prevent SARS-CoV-2 invasion.

High infection caused by mutations of SARS-CoV-2 calls for new prevention strategy. Ganoderma lucidum known as a superior immunoenhancer exhibits various antiviral effects, whether it can resist SARS-CoV-2 remains unclear. Herein, virtual screening combined with in vitro hACE2 inhibition assays were used to investigate its anti SARS-CoV-2 effect. Potential 54 active components, 80 core targets and 20 crucial pathways were identified by the component-target-pathway network. The binding characters of these components to hACE2 and its complexes with spike protein including omicron variant was analyzed by molecular docking. Lucidenic acid A was selected as the top molecule with high affinity to all receptors by forming hydrogen bonds. Molecular dynamics simulation showed it had good binding stability with the receptor proteins. Finally, in vitro FRET test demonstrated it inhibited the hACE2 activity with IC50 2 µmol/mL. Therefore, lucidenic acid A can prevent the virus invasion by blocking hACE2 binding with SARS-CoV-2.

Pharmacological Properties and Molecular Targets of Alisol Triterpenoids from Alismatis Rhizoma.

More than 100 protostane triterpenoids have been isolated from the dried rhizomes of Alisma species, designated Alismatis rhizoma (AR), commonly used in Asian traditional medicine to treat inflammatory and vascular diseases. The main products are the alisols, with the lead compounds alisol-A/-B and their acetate derivatives being the most abundant products in the plant and the best-known bioactive products. The pharmacological effects of Ali-A, Ali-A 24-acetate, Ali-B, Ali-B 23-acetate, and derivatives have been analyzed to provide an overview of the medicinal properties, signaling pathways, and molecular targets at the origin of those activities. Diverse protein targets have been proposed for these natural products, including the farnesoid X receptor, soluble epoxide hydrolase, and other enzymes (AMPK, HCE-2) and functional proteins (YAP, LXR) at the origin of the anti-atherosclerosis, anti-inflammatory, antioxidant, anti-fibrotic, and anti-proliferative activities. Activities were classified in two groups. The lipid-lowering and anti-atherosclerosis effects benefit from robust in vitro and in vivo data (group 1). The anticancer effects of alisols have been largely reported, but, essentially, studies using tumor cell lines and solid in vivo data are lacking (group 2). The survey shed light on the pharmacological properties of alisol triterpenoids frequently found in traditional phytomedicines.

A review on triterpenoids from plant sources as potential antiviral agents

Viral infections are considered as leading a health issue globally. Numerous numbers of biologically active anti-viral agents have been identified from plants and other organisms. Particularly, terpenoids are a major component of the plant secondary metabolites and a complexity of these structures is accompanied by the potency of their biological activities. It is believed that most of the terpenoids possess the bioactivity against viral infections and cancer diseases. Hence, affected by the pressing a need elevated by the spreading of seriously life-threaten viruses, this review highlights the importance of terpenoids and their activity as antiviral agents that can be employed to treat current lethal diseases such as HIV, H1N1, SARS-CoV and HSV.

Mechanism of Huoxiang Zhengqi oral liquid in the treatment of COVID-19 based on biological information technology

Objective: To explore the network regulation mechanism of Huoxiang Zhengqi Oral Liquid(HXZQ) in the treatment of coronavirus disease 19 (COVID-19).

In silico studies to identify potential natural antiviral agents to treat and control SARS-CoV-2 (COVID-19). (Special Issue: Covid-19 in India.)

Background: Recently, a new and fatal strain of coronavirus named as SARS-CoV-2 (Disease: COVID-19) appeared in Wuhan, China in December of 2019 and was officially named severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) by the International Committee on Taxonomy of Viruses based on phylogenetic analysis. Because of its highly contagious nature, there is an urgent need for suitable drug which can control the viral infection. The covid 19 main protease was found to be the best target for drug synthesis as it involved in viral replication.

Anti-COVID-19 and antidiabetic activities of new oleanane and ursane-type triterpenoids from Salvia grossheimii: an in-silico approach.

Salvia grossheimii is a perennial herb with antidiabetic and cytotoxic constituents. In continuation of our study on S. grosshiemii to identify the bioactive phytochemicals, we have reported the characterization of seven undescribed triterpenoids. The aerial parts of the plant were extracted in dichloromethane and its constituents were isolated using chromatography techniques. The structures of compounds were identified using 1D, 2D NMR, and ESI-MS spectral data. Seven new oleanane- and ursane-type triterpenoids (1-7) were identified in S. grossheimii. The structures of 1-7 were characterized as; 2α-hydroxy-3ß-acetoxy-olean-9(11),12-diene (1), 2α-acetoxy-3ß-hydroxy-olean-9(11),12-diene (2), 3ß-acetoxy-olean-18-ene,2α,11α-diol (3), 2α-hydroxy-3ß-acetoxy-urs-9(11),12-diene (4), 2α-acetoxy-3ß-hydroxy-urs-9(11),12-diene (5), 2α,3ß-diacetoxy-urs-12-ene-11α,20ß-diol (6), 2α,3ß-diacetoxy-urs-9(11),12-diene-20ß-ol (7). Triterpenoids (2, 5, and 7) were intramolecular transesterification or dehydration products of their corresponding isomers or allylic alcohol in the C rings, respectively, produced in-situ during NMR spectroscopy. Virtual screening of 1-7 was performed with molecular docking analysis to identify the potential SARS-CoV-2 and α-glucosidase inhibitors using the smina molecular docking algorithm. The best binding energy values (kcal/mol) against COVID-19 main protease Mpro were calculated for 6 (-8.77) and 7 (-8.68), and the higher binding affinities toward human α-glucosidase were obtained for 2 (-9.39) and 6 (-8.63). This study suggests S. grossheimii as a rich source of bioactive triterpenoids and introduces new natural compounds. Considering the high binding energy values of 2, 6, and 7, these structures could be candidates for anti-COVID-19 and antidiabetic drug development in the future.

Exploring the therapeutic nature of limonoids and triterpenoids against SARS-CoV-2 by targeting nsp13, nsp14, and nsp15 through molecular docking and dynamics simulations.

BACKGROUND AND AIM: The ongoing global pandemic due to SARS-CoV-2 caused a medical emergency. Since December 2019, the COVID-19 disease is spread across the globe through physical contact and respiratory droplets. Coronavirus caused a severe effect on the human immune system where some of the non-structural proteins (nsp) are involved in virus-mediated immune response and pathogenesis. To suppress the viral RNA replication mechanism and immune-mediated responses, we aimed to identify limonoids and triterpenoids as antagonists by targeting helicases (nsp13), exonuclease (nsp14), and endoribonuclease (nsp15) of SARS-CoV-2 as therapeutic proteins. EXPERIMENTAL PROCEDURE: In silico molecular docking and drug-likeness of a library of 369 phytochemicals from limonoids and triterpenoids were performed to screen the potential hits that binds effectively at the active site of the proteins target. In addition, the molecular dynamics simulations of the proteins and their complexes with the potential hits were performed for 100 ns by using GROMACS. RESULTS AND CONCLUSION: The potential compounds 26-deoxyactein and 25-O-anhydrocimigenol 3-O-beta-d-xylopyranoside posing strong interactions with a minimum binding energy of -10.1 and -9.5 kcal/mol, respectively and sustained close contact with nsp13 for 100 ns. The nsp14 replication fork activity was hindered by the tomentosolic acid, timosaponin A-I, and shizukaol A with the binding affinity score of -9.2, -9.2, and -9.0 kcal/mol, respectively. The nsp15 endoribonuclease catalytic residues were inhibited potentially by limonin, 25-O-anhydrocimigenol 3-O-alpha-l-arabinopyranoside, and asperagenin posing strong binding affinity scores of -9.0, -8.8, and -8.7 kcal/mol, respectively. Computationally predicted potential phytochemicals for SARS-CoV-2 are known to possess various medicinal properties.

HISTO-ANATOMICAL STUDIES IN TUSSILAGO FARFARA L. A SPECIES WITH MEDICINAL POTENTIAL AGAINST RESPIRATORY DISEASES

This study aimed to describe the histo-anatomy of Tussilago farfara L. species from the Asteraceae family, with medicinal importance in Romania for the alternative treatment of respiratory diseases (asthma, laryngitis, cough, emphysema) and other disorders. The chemical composition of Coltsfoot includes more than 150 chemical substances (triterpenoids, sesquiterpenoids, alkaloids) with different medicinal proprieties (expectorant, antimicrobial, antitussive) and contraindications (pregnancy, lactation, hepatic disorders). The vegetal material used in this study was collected from the waterside of river Sireţel in the village Sireţel from Sireţel commune in Iaşi County. The cross-sections were performed manually through vegetative organs (rhizome, stem, and leaf) with the help of a hand microtome and a botanic razor. The structures of the sections were highlighted by double coloration (iodine green and ruthenium red), the observation was performed on a Novex microscope. The characteristics structures observed by us (epidermis, vascular bundles, trichomes, angular collenchyma, assimilating parenchyma, stomata, mesophyll) correspond with Toma and Rugină (1998) observations and descriptions.

Antimicrobial Triterpenoids and Ingol Diterpenes from Propolis of Semi-Arid Region of Morocco.

The chemical composition and antimicrobial activity of propolis from a semi-arid region of Morocco were investigated. Fifteen compounds, including triterpenoids (1, 2, 7-12), macrocyclic diterpenes of ingol type (3-6) and aromatic derivatives (13-15), were isolated by various chromatographic methods. Their structures were elucidated by a combination of spectroscopic and chiroptical methods. Compounds 1 and 3 are new natural compounds, and 2, 4-6, and 9-11 are newly isolated from propolis. Moreover, the full nuclear magnetic resonance (NMR) assignments of three of the known compounds (2, 4 and 5) were reported for the first time. Most of the compounds tested, especially the diterpenes 3, 4, and 6, exhibited very good activity against different strains of bacteria and fungi. Compound 3 showed the strongest activity with minimum inhibitory concentrations (MICs) in the range of 4-64 µg/mL. The combination of isolated triterpenoids and ingol diterpenes was found to be characteristic for Euphorbia spp., and Euphorbia officinarum subsp. echinus could be suggested as a probable and new plant source of propolis.

Syzygium aromaticum as a possible source of SARS-CoV-2 main protease inhibitors: evidence from a computational investigation

SARS-CoV-2, a new and fast circulating coronavirus strain, infected over 214 countries and territories worldwide and caused global health emergencies. The absence of appropriate medicines and vaccinations has further complicated the condition. SARS-CoV-2 main protease (Mpro) is crucial for its propagation, and it is considered a striking target. This study used several computational approaches to determine the probable antagonist of SARS-CoV-2 Mpro from bioactive phytochemicals of Syzygium aromaticum. A total of 20 compounds were screened through in silico approach. The molecular dynamics simulation studies were then carried out for further insights. We found crategolic acid, oleanolic acid, and kaempferol have considerable binding affinity and important molecular contacts with catalytic pocket residues, His41-Cys145. The pharmacological properties through ADMET analysis also showed that these compounds could be used as safe drug candidates. The molecular dynamics simulation study further confirmed these compound's stability with Mpro. However, further detailed in-vitro and in-vivo analyses are compulsory to evaluate the real potentiality of identified compounds.

Terpenoids from Centella asiatica, a novel inhibitor against RNA-dependent-RNA polymerase activity of NSP12 of the SARS CoV-2 (COVID-19)

Covid-19, the first case of which was reported in Wuhan (China) in December 2019 was found to be a strain of coronaviruses like SARS and MERS reported earlier. These viruses are positive strain RNA viruses composed of both structural as well as non-structural proteins. The enzyme RdRp (RNA dependent RNA polymerase) stands responsible for catalyzing the replication of this virus within the host cell. A disruption in the core catalytic subunit composed of nsp12, nsp7, and nsp8 may inhibit the replication of the same. Different drugs targeting different sites on the virus have been developed. In this context, some of the natural products of the plant Centella asiatica was lead for further drug development against the target proteins of RdRp protein (PDB ID: 6NUR) through molecular docking. These compounds are 2,3-dihydroxyurs-12-en-28-oic acid, corosolic acid and pomolic acid which are triterpenoids and have highest binding affinity against RdRp protein thereby arresting the viral replication. Several previous studies showed triterpenoids as pertinent mediators implicated in the in vitro immune response.

New Investigations with Lupane Type A-Ring Azepane Triterpenoids for Antimycobacterial Drug Candidate Design.

Twenty lupane type A-ring azepano-triterpenoids were synthesized from betulin and its related derivatives and their antitubercular activity against Mycobacterium tuberculosis, mono-resistant MTB strains, and nontuberculous strains Mycobacterium abscessus and Mycobacterium avium were investigated in the framework of AToMIc (Anti-mycobacterial Target or Mechanism Identification Contract) realized by the Division of Microbiology and Infectious Diseases, NIAID, National Institute of Health. Of all the tested triterpenoids, 17 compounds showed antitubercular activity and 6 compounds were highly active on the H37Rv wild strain (with MIC 0.5 µM for compound 7), out of which 4 derivatives also emerged as highly active compounds on the three mono-resistant MTB strains. Molecular docking corroborated with a machine learning drug-drug similarity algorithm revealed that azepano-triterpenoids have a rifampicin-like antitubercular activity, with compound 7 scoring the highest as a potential M. tuberculosis RNAP potential inhibitor. FIC testing demonstrated an additive effect of compound 7 when combined with rifampin, isoniazid and ethambutol. Most compounds were highly active against M. avium with compound 14 recording the same MIC value as the control rifampicin (0.0625 µM). The antitubercular ex vivo effectiveness of the tested compounds on THP-1 infected macrophages is correlated with their increased cell permeability. The tested triterpenoids also exhibit low cytotoxicity and do not induce antibacterial resistance in MTB strains.

Effects of Topically Applied Betulinic Acid and NVX-207 on Melanocytic Tumors in 18 Horses.

The naturally occurring betulinic acid (BA) and its derivative NVX-207 induce apoptosis in equine melanoma cells in vitro. After topical application, high concentrations of the substances can be reached in healthy equine skin. With the aim to investigate the effect and safety of topically applied BA and NVX-207 in horses with melanocytic tumors, the longitudinal, prospective, randomized, double-blind, placebo-controlled study protocol included eighteen Lipizzaner mares with early-stage cutaneous melanoma assigned to three groups. Melanocytic lesions were topically treated either with a placebo, 1% BA or 1% NVX-207 twice a day for 91 days. Caliper measurements, clinical examinations and blood tests were performed to assess the effects and safety of the medication. The topical treatment was convenient and safe. The volumes of tumors treated with BA were significantly reduced over time as compared to tumors treated with the placebo from day 80 of the study. Although treatment with NVX-207 seemed to decrease tumor volume, these results did not reach statistical significance. The findings must be regarded as preliminary due to the limited group size and need to be replicated in a larger cohort with modified pharmaceutical test formulations. Accordingly, the treatment protocol cannot yet be recommended in its current form.

In Vitro Anti-HIV-1 Reverse Transcriptase and Integrase Properties of Punica granatum L. Leaves, Bark, and Peel Extracts and Their Main Compounds.

In a search for natural compounds with anti-HIV-1 activity, we studied the effect of the ethanolic extract obtained from leaves, bark, and peels of Punica granatum L. for the inhibition of the HIV-1 reverse transcriptase (RT)-associated ribonuclease H (RNase H) and integrase (IN) LEDGF-dependent activities. The chemical analyses led to the detection of compounds belonging mainly to the phenolic and flavonoid chemical classes. Ellagic acid, flavones, and triterpenoid molecules were identified in leaves. The bark and peels were characterized by the presence of hydrolyzable tannins, such as punicalins and punicalagins, together with ellagic acid. Among the isolated compounds, the hydrolyzable tannins and ellagic acid showed a very high inhibition (IC50 values ranging from 0.12 to 1.4 µM and 0.065 to 0.09 µM of the RNase H and IN activities, respectively). Of the flavonoids, luteolin and apigenin were found to be able to inhibit RNase H and IN functions (IC50 values in the 3.7-22 µM range), whereas luteolin 7-O-glucoside showed selective activity for HIV-1 IN. In contrast, betulinic acid, ursolic acid, and oleanolic acid were selective for the HIV-1 RNase H activity. Our results strongly support the potential of non-edible P. granatum organs as a valuable source of anti-HIV-1 compounds.

Multifunctional inhibitors of SARS-CoV-2 by MM/PBSA, essential dynamics, and molecular dynamic investigations.

The ongoing COVID-19 pandemic demands a novel approach to combat and identify potential therapeutic targets. The SARS-CoV-2 infection causes a hyperimmune response followed by a spectrum of diseases. Limonoids are a class of triterpenoids known to prevent the release of IL-6, IL-15, IL-1α, IL-1ß via TNF and are also known to modulate PI3K/Akt/GSK-3ß, JNK1/2, MAPKp38, ERK1/2, and PI3K/Akt/mTOR signaling pathways and could help to avoid viral infection, persistence, and pathogenesis. The present study employs a computational approach of virtual screening and molecular dynamic (MD) simulations of such compounds against RNA-dependent RNA polymerase (RdRp), Main protease (Mpro), and Papain-like protease (PLpro) of SARS-CoV-2. MD simulation, Molecular Mechanics Poisson-Boltzmann Surface Area (MM/PBSA), and Essential dynamics revealed that the macromolecule-ligand complexes are stable with very low free energy of binding. Such compounds that could modulate both host responses and inhibit viral machinery could be beneficial in effectively controlling the global pandemic.