Interaction of the renin inhibitor aliskiren with the SARS-CoV-2 main protease: a molecular docking study.

The renin protein is an upstream enzymatic regulator of the renin-aldosterone-angiotensin system (RAAS) essential for the maintenance of blood pressure. The angiotensin-converting enzyme-2 (ACE2) is a major component of the RAAS and a cell surface receptor exploited by the SARS-CoV-2 virus to enter host cells. A recent molecular modeling study has revealed that the direct renin peptide inhibitor remikiren can bind to the catalytic site of SARS-CoV-2 main protease (Mpro). By analogy, we postulated that the non-peptidic drug aliskiren, a more potent renin inhibitor than remikiren and a drug routinely used to treat hypertension, may also be able to interact with Mpro. An in silico comparison of the binding of the two compounds to Mpro indicates that aliskiren (ΔE = -75.9 kcal/mol) can form stable complexes with the main viral protease, binding to the active site, as remikiren (ΔE = -83.2 kcal/mol). The comparison with a panoply of 30 references compounds (mainly antiviral drugs) indicated that remikiren is a potent Mpro binder comparable to drugs like glecaprevir and pibrentasvir (ΔE = -96.5 kcal/mol). The energy of interaction (ΔE) of aliskiren with Mpro is about 10% lower than with remikiren, comparable to that calculated with drugs like velpatasvir and sofosbuvir. A model is proposed to define the drug binding site, with the best binders (including remikiren) penetrating deeply into the site, whereas the less potent binders (including aliskiren) interact more superficially with the protein.Communicated by Ramaswamy H. Sarma.

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.

Interaction of panduratin A and derivatives with the SARS-CoV-2 main protease (mpro): a molecular docking study.

Panduratin A (Pa-A) is a prenylated cyclohexenyl chalcone isolated from the rhizomes of the medicinal and culinary plant Boesenbergia rotunda (L.) Mansf., commonly called fingerroots. Both an ethanolic plant extract and Pa-A have shown a marked antiviral activity against the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), responsible for the COVID-19 pandemic disease. Pa-A functions as a protease inhibitor inhibiting infection of human cells by the virus. We have modeled the interaction of Pa-A, and 26 panduratin analogues with the main protease (Mpro) of SARS-CoV-2 using molecular docking. The natural product 4-hydroxypanduratin showed a higher Mpro binding capacity than Pa-A and isopanduratin A. The interaction with MPro of all known panduratin derivatives (Pa-A to Pa-Y) have been compared, together with more than 60 reference products. Three compounds emerged as potential robust MPro binders: Pa-R, Pa-V, Pa-S, with a binding capacity significantly higher than 4-OH-Pa-A and Pa-A. The empirical energy of interaction (ΔE) calculated with the best compound in the panduratin series, Pa-R bound to Mpro, surpassed that measured with the top reference protease inhibitors such a ruprintrivir, lufotrelvir, and glecaprevir. Structure-binding relationships are discussed. Compounds with a flavanone moiety (PA-R/S) are the best binders, better than those with a chromene unit (Pa-F/G). The extended molecules (such as Pa-V) exhibit good Mpro binding, but the dimeric compound Pa-Y is too long and protrudes outside the binding cavity. The work provides novel ideas to guide the design of new molecules interacting with Mpro.Communicated by Ramaswamy H. Sarma.

Panduratin A is the main bioactive molecule in extracts of the medicinal plant Boesenbergia rotunda.Extracts of B. rotunda and Pa-A have shown activity against the virus SARS-CoV-2.We modeled the interaction of 27 panduratin derivatives with the main protease (M^pro) of the virus.Three molecules (Pa-R/V/S) revealed high M^pro binding capacity compared to reference compounds.Structure­binding relationships are discussed, to guide the design of compounds to treat COVID-19.

A world tour in the name of natural products.

BACKGROUND: Names of natural products (NP) are usually given depending on the species of origin, be it a plant, a marine organism or a microbial species. In some cases, names have been given with reference to people, animals, music, foods or places. Many NP refer to countries, cities or specific places such as mountains, deserts, seas and oceans. PURPOSE: On the basis of NP names, a world tour has been imagined referring to more than one hundred NP with names evocative of over 50 countries and regions. RESULTS: The world tour goes from UK (britannin) to Italy (vaticanol) in Europe, from Uganda (ugandoside) to Senegal (senegalene, senegalenines) in Africa, from Brazil (brasilin) to Chile (santiaguine) in South America, from Utah (utahin) to Florida (floridanolide) in the US. It includes Central America (mexicanin, panamine) and the Caribbean islands (jamaicin, bahamaolides). It also crosses Alaska (alaskene) and Canada (quebecol, canadaline). The tour continues throughout Asia, from Thailand (thailandine) to China (Chinaldine) and Pakistan (pakistanamine), to finally reaches Oceania with Australia (australigenin) and Vanuatu (vanuatine), among other countries. This virtual journey, without bordure or wall, brings us to the highest mountains (himalayamine), the deepest oceans (pacificins) and the largest deserts (desertomycin). CONCLUSION: In the current period of COVID-19 pandemia, with restricted opportunities for international travels, this NP name-based virtual journey offers a world tour to learn more from nature and to inspire scientists to contribute to the field of NP discovery and drug design. There are also limitations associated with the use of trivial names for NP. NP names can be further exploited for teaching and learning.

In silico analysis of echinocandins binding to the main proteases of coronaviruses PEDV (3CLpro) and SARS-CoV-2 (Mpro).

The porcine epidemic diarrhea virus (PEDV) and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) are two highly pathogenic viruses causing tremendous damages to the swine and human populations, respectively. Vaccines are available to prevent contamination and to limit dissemination of these two coronaviruses, but efficient and widely affordable treatments are needed. Recently, four natural products targeting the 3C-like protease (3CLpro) of PEDV and inhibiting replication of the virus in vitro have been identified: tomatidine, epigallocatechin-3-gallate, buddlejasaponin IVb and pneumocandin B0. We have evaluated the interaction of these compounds with 3CLpro of PEDV and with the structurally similar main protease (Mpro) of SARS-CoV-2. The molecular docking analysis indicated that the echinocandin-type lipopeptide pneumocandin B0 can generate much more stable complexes with both proteases compared to tomatidine. The empirical energy of interaction (ΔE) calculated with pneumocandin B0 bound to Mpro is extremely high, comparable to that measured with known antiviral drugs. Pneumocandin B0 and its analogue capsofungin appeared a little less adapted to interact with 3CLpro compared to Mpro. In contrast, the antifungal drug micafungin bearing an unfused tricyclic side chain, emerges as a better ligand of 3CLpro of PEDV compared to Mpro of SARS-CoV-2, based on our calculations. Collectively, the analysis underlines the benefit of echinocandin-type antifungal drugs as potential inhibitors of PEDV and SARS-CoV-2 main proteases. These clinically important antifungal natural products deserve further studies as antiviral agents.

A new horizon for the old antibacterial drug clofoctol.

The synthetic antibacterial drug clofoctol (CFT) has long been used to treat respiratory tract infections in Europe. In recent years, the drug was found to target two biologically important proteins, the Cdc7/Dbf4 protein kinase complex and the mRNA-binding protein cold shock domain containing E1 (CSDE1), also known as upstream-of-N-Ras protein (UNR). These interactions are at the origin of the antitumor activity of CFT, recently evidenced in prostate cancer and neuroglioma. Drug-protein binding models provide a structural basis to guide the design of more potent anticancer compounds. A renewed interest in CFT can be anticipated for the treatment of cancers, and possibly Coronavirus 2019 (COVID-19).

Mechanistic insights into dimethyl cardamonin-mediated pharmacological effects: A double control of the AMPK-HMGB1 signaling axis.

Dimethyl cardamonin (DMC) has been isolated from diverse plants, notably from Cleistocalyx operculatus. We have reviewed the pharmacological properties of this natural product which displays anti-inflammatory, anti-hyperglycemic and anti-cancer properties. The pharmacological activities essentially derive from the capacity of DMC to interact with the protein targets HMGB1 and AMPK. Upon binding to HMGB1, DMC inhibits the nucleocytoplasmic transfer of the protein and its extracellular secretion, thereby blocking its alarmin function. DMC also binds to the AMP site of AMPK to activate phospho-AMPK and then to trigger downstream signals leading to the anti-inflammatory and anti-hyperglycemic effects. AMPK activation by DMC reinforces inhibition of HMGB1, to further reduce the release of the alarmin protein, likely contributing to the anticancer effects. The characterization of a tight control of DMC over the AMPK-HMGB1 axis not only helps to explain the known activities of DMC but also suggests opportunities to use this chalcone to treat other pathological conditions such as the acute respiratory distress syndrome (which affects patients with COVID-19). DMC structural analogues are also evoked.

Glycyrrhizin: An alternative drug for the treatment of COVID-19 infection and the associated respiratory syndrome?

Safe and efficient drugs to combat the current COVID-19 pandemic are urgently needed. In this context, we have analyzed the anti-coronavirus potential of the natural product glycyrrhizic acid (GLR), a drug used to treat liver diseases (including viral hepatitis) and specific cutaneous inflammation (such as atopic dermatitis) in some countries. The properties of GLR and its primary active metabolite glycyrrhetinic acid are presented and discussed. GLR has shown activities against different viruses, including SARS-associated Human and animal coronaviruses. GLR is a non-hemolytic saponin and a potent immuno-active anti-inflammatory agent which displays both cytoplasmic and membrane effects. At the membrane level, GLR induces cholesterol-dependent disorganization of lipid rafts which are important for the entry of coronavirus into cells. At the intracellular and circulating levels, GLR can trap the high mobility group box 1 protein and thus blocks the alarmin functions of HMGB1. We used molecular docking to characterize further and discuss both the cholesterol- and HMG box-binding functions of GLR. The membrane and cytoplasmic effects of GLR, coupled with its long-established medical use as a relatively safe drug, make GLR a good candidate to be tested against the SARS-CoV-2 coronavirus, alone and in combination with other drugs. The rational supporting combinations with (hydroxy)chloroquine and tenofovir (two drugs active against SARS-CoV-2) is also discussed. Based on this analysis, we conclude that GLR should be further considered and rapidly evaluated for the treatment of patients with COVID-19.