Molecular Docking and Dynamic Simulation Revealed the Potential Inhibitory Activity of Opioid Compounds Targeting the Main Protease of SARS-CoV-2.

Opioids are a class of chemicals, naturally occurring in the opium poppy plant, and act on the brain to cause a range of impacts, notably analgesic and anti-inflammatory actions. Moreover, an overview was taken in consideration for SARS-CoV-2 incidence and complications, as well as the medicinal uses of opioids were discussed being a safe analgesic and anti-inflammatory drug in a specific dose. Also, our article focused on utilization of opioids in the medication of SARS-CoV-2. Therefore, the major objective of this study was to investigate the antiviral effect of opioids throughout an in silico study by molecular docking study to fifteen opioid compounds against SARS-CoV-2 main protease (PDB ID 6LU7, Mpro). The docking results revealed that opioid complexes potentially inhibit the Mpro active site and exhibiting binding energy (-11.0 kcal/mol), which is comparably higher than the ligand. Furthermore, ADMET prediction indicated that all the tested compounds have good oral absorption and bioavailability and can transport via biological membranes. Finally, Mpro-pholcodine complex was subjected to five MD (RMSD, RMSF, SASA, Rg, and hydrogen bonding) and two MM-PBSA, and conformational change studies, for 100 ns, confirmed the stability of pholcodine, as a representative example, inside the active site of Mpro.

The Discovery of Potential SARS-CoV-2 Natural Inhibitors among 4924 African Metabolites Targeting the Papain-like Protease: A Multi-Phase In Silico Approach.

Four compounds, hippacine, 4,2'-dihydroxy-4'-methoxychalcone, 2',5'-dihydroxy-4-methoxychalcone, and wighteone, were selected from 4924 African natural metabolites as potential inhibitors against SARS-CoV-2 papain-like protease (PLpro, PDB ID: 3E9S). A multi-phased in silico approach was employed to select the most similar metabolites to the co-crystallized ligand (TTT) of the PLpro through molecular fingerprints and structural similarity studies. Followingly, to examine the binding of the selected metabolites with the PLpro (molecular docking. Further, to confirm this binding through molecular dynamics simulations. Finally, in silico ADMET and toxicity studies were carried out to prefer the most convenient compounds and their drug-likeness. The obtained results could be a weapon in the battle against COVID-19 via more in vitro and in vivo studies.

Discovery of Potential SARS-CoV-2 Papain-like Protease Natural Inhibitors Employing a Multi-Phase In Silico Approach.

As an extension of our research against COVID-19, a multiphase in silico approach was applied in the selection of the three most common inhibitors (Glycyrrhizoflavone (76), Arctigenin (94), and Thiangazole (298)) against papain-like protease, PLpro (PDB ID: 4OW0), among 310 metabolites of natural origin. All compounds of the exam set were reported as antivirals. The structural similarity between the examined compound set and S88, the co-crystallized ligand of PLpro, was examined through structural similarity and fingerprint studies. The two experiments pointed to Brevicollin (28), Cryptopleurine (41), Columbamine (46), Palmatine (47), Glycyrrhizoflavone (76), Licochalcone A (87), Arctigenin (94), Termilignan (98), Anolignan B (99), 4,5-dihydroxy-6″-deoxybromotopsentin (192), Dercitin (193), Tryptanthrin (200), 6-Cyano-5-methoxy-12-methylindolo [2, 3A] carbazole (211), Thiangazole (298), and Phenoxan (300). The binding ability against PLpro was screened through molecular docking, disclosing the favorable binding modes of six metabolites. ADMET studies expected molecules 28, 76, 94, 200, and 298 as the most favorable metabolites. Then, molecules 76, 94, and 298 were chosen through in silico toxicity studies. Finally, DFT studies were carried out on glycyrrhizoflavone (76) and indicated a high level of similarity in the molecular orbital analysis. The obtained data can be used in further in vitro and in vivo studies to examine and confirm the inhibitory effect of the filtered metabolites against PLpro and SARS-CoV-2.

Isolation and In Silico Inhibitory Potential against SARS-CoV-2 RNA Polymerase of the Rare Kaempferol 3-O-(6″-O-acetyl)-Glucoside from Calligonum tetrapterum.

The phytochemical constituents of Calligonum tetrapterum Jaub. & Spach (Family Polygonaceae) were studied for the first time. The study resulted in the isolation of the rare flavonol glycoside, kaempferol 3-O-(6″-O-acetyl)-glucoside,(K3G-A). The potential inhibitive activity of K3G-A toward SARS-CoV-2 was investigated utilizing several in silico approaches. First, molecular fingerprints and structural similarity experiments were carried out for K3G-A against nine co-crystallized ligands of nine proteins of SARS-CoV-2 to reveal if there is a structural similarity with any of them. The conducted studies showed the high similarity of K3G-A and remdesivir, the co-crystallized ligand of SARS-CoV-2 RNA-dependent RNA polymerase (PDB ID: 7BV2), RdRp. To validate these findings, a DFT study was conducted and confirmed the proposed similarity on the electronic and orbital levels. The binding of K3G-A against RdRp was confirmed through molecular docking studies exhibiting a binding energy of -27.43 kcal/mol, which was higher than that of remdesivir. Moreover, the RdRp-K3G-A complex was subjected to several MD studies at 100 ns that authenticated the accurate mode of binding and the correct dynamic behavior. Finally, in silico ADMET and toxicity evaluation of K3G-A was conducted and denoted the safety and the drug-likeness of K3G-A. In addition to K3G-A, two other metabolites were isolated and identified to be kaempferol (K) and ß-sitosterol (ß-S).

A Multistage In Silico Study of Natural Potential Inhibitors Targeting SARS-CoV-2 Main Protease.

Among a group of 310 natural antiviral natural metabolites, our team identified three compounds as the most potent natural inhibitors against the SARS-CoV-2 main protease (PDB ID: 5R84), Mpro. The identified compounds are sattazolin and caprolactin A and B. A validated multistage in silico study was conducted using several techniques. First, the molecular structures of the selected metabolites were compared with that of GWS, the co-crystallized ligand of Mpro, in a structural similarity study. The aim of this study was to determine the thirty most similar metabolites (10%) that may bind to the Mpro similar to GWS. Then, molecular docking against Mpro and pharmacophore studies led to the choice of five metabolites that exhibited good binding modes against the Mpro and good fit values against the generated pharmacophore model. Among them, three metabolites were chosen according to ADMET studies. The most promising Mpro inhibitor was determined by toxicity and DFT studies to be caprolactin A (292). Finally, molecular dynamics (MD) simulation studies were performed for caprolactin A to confirm the obtained results and understand the thermodynamic characteristics of the binding. It is hoped that the accomplished results could represent a positive step in the battle against COVID-19 through further in vitro and in vivo studies on the selected compounds.

Multi-Step In Silico Discovery of Natural Drugs against COVID-19 Targeting Main Protease.

In continuation of our antecedent work against COVID-19, three natural compounds, namely, Luteoside C (130), Kahalalide E (184), and Streptovaricin B (278) were determined as the most promising SARS-CoV-2 main protease (Mpro) inhibitors among 310 naturally originated antiviral compounds. This was performed via a multi-step in silico method. At first, a molecular structure similarity study was done with PRD_002214, the co-crystallized ligand of Mpro (PDB ID: 6LU7), and favored thirty compounds. Subsequently, the fingerprint study performed with respect to PRD_002214 resulted in the election of sixteen compounds (7, 128, 130, 156, 157, 158, 180, 184, 203, 204, 210, 237, 264, 276, 277, and 278). Then, results of molecular docking versus Mpro PDB ID: 6LU7 favored eight compounds (128, 130, 156, 180, 184, 203, 204, and 278) based on their binding affinities. Then, in silico toxicity studies were performed for the promising compounds and revealed that all of them have good toxicity profiles. Finally, molecular dynamic (MD) simulation experiments were carried out for compounds 130, 184, and 278, which exhibited the best binding modes against Mpro. MD tests revealed that luteoside C (130) has the greatest potential to inhibit SARS-CoV-2 main protease.

The Computational Preventive Potential of the Rare Flavonoid, Patuletin, Isolated from Tagetes patula, against SARS-CoV-2.

The rare flavonoid, patuletin, was isolated from the flowers of Tagetes patula growing in Egypt. The rarity of the isolated compound inspired us to scrutinize its preventive effect against COVID-19 utilizing a multi-step computational approach. Firstly, a structural similarity study was carried out against nine ligands of nine SARS-CoV-2 proteins. The results showed a large structural similarity between patuletin and F86, the ligand of SARS-CoV-2 RNA-dependent RNA polymerase (RdRp). Then, a 3D-Flexible alignment study of patuletin and F86 verified the proposed similarity. To determine the binding opportunity, patuletin was docked against the RdRp showing a correct binding inside its active pocket with an energy of -20 kcal/mol that was comparable to that of F86 (-23 kcal/mol). Following, several MD simulations as well as MM-PBSA studies authenticated the accurate binding of patuletin in the RdRp via the correct dynamic and energetic behaviors over 100 ns. Additionally, in silico ADMET studies showed the general safety and drug-likeness of patuletin.

Olive Leaves as a Potential Phytotherapy in the Treatment of COVID-19 Disease; A Mini-Review.

Beginning from December 2019, widespread COVID-19 has caused huge financial misfortunes and exceptional wellbeing emergencies across the globe. Discovering an effective and safe drug candidate for the treatment of COVID-19 and its associated symptoms became an urgent global demand, especially due to restricted information that has been discharged with respect to vaccine efficacy and safety in humans. Reviewing the recent research, olive leaves were selected as a potential co-therapy supplement for the treatment and improvement of clinical manifestations in COVID-19 patients. Olive leaves were reported to be rich in phenolic compounds such as oleuropein, hydroxytyrosol, verbascoside, apigenin-7-O-glucoside, and luteolin-7-O-glucoside and also triterpenoids such as maslinic, ursolic, and oleanolic acids that have been reported as anti-SARS-CoV-2 metabolites in recent computational and in vitro studies. In addition, olive leaf extract was previously reported in several in vivo studies for its anti-inflammatory, analgesic, antipyretic, immunomodulatory, and antithrombotic activities which are of great benefit in the control of associated inflammatory cytokine storm and disseminated intravascular coagulation in COVID-19 patients. In conclusion, the described biological activities of olive leaves alongside their biosafety, availability, and low price make them a potential candidate drug or supplement to control COVID-19 infection and are recommended for clinical investigation.

Isolation and In Silico SARS-CoV-2 Main Protease Inhibition Potential of Jusan Coumarin, a New Dicoumarin from Artemisia glauca.

A new dicoumarin, jusan coumarin, (1), has been isolated from Artemisia glauca aerial parts. The chemical structure of jusan coumarin was estimated, by 1D, 2D NMR as well as HR-Ms spectroscopic methods, to be 7-hydroxy-6-methoxy-3-[(2-oxo-2H-chromen-6-yl)oxy]-2H-chromen-2-one. As the first time to be introduced in nature, its potential against SARS-CoV-2 has been estimated using various in silico methods. Molecular similarity and fingerprints experiments have been utilized for 1 against nine co-crystallized ligands of COVID-19 vital proteins. The results declared a great similarity between Jusan Coumarin and X77, the ligand of COVID-19 main protease (PDB ID: 6W63), Mpro. To authenticate the obtained outputs, a DFT experiment was achieved to confirm the similarity of X77 and 1. Consequently, 1 was docked against Mpro. The results clarified that 1 bonded in a correct way inside Mpro active site, with a binding energy of -18.45 kcal/mol. Furthermore, the ADMET and toxicity profiles of 1 were evaluated and showed the safety of 1 and its likeness to be a drug. Finally, to confirm the binding and understand the thermodynamic characters between 1 and Mpro, several molecular dynamics (MD) simulations studies have been administered. Additionally, the known coumarin derivative, 7-isopentenyloxycoumarin (2), has been isolated as well as ß-sitosterol (3).

A Systematic Review of the Global Intervention for SARS-CoV-2 Combating: From Drugs Repurposing to Molnupiravir Approval

The rising outbreak of SARS-CoV-2 continues to unfold all over the world. The development of novel effective antiviral drugs to fight against SARS-CoV-2 is a time cost. As a result, some specific FDA-approved drugs have already been repurposed and authorized for COVID-19 treatment. The repurposed drugs used were either antiviral or non-antiviral drugs. Accordingly, the present review thoroughly focuses on the repurposing efficacy of these drugs including clinical trials experienced, the combination therapies used, the novel methods followed for treatment, and their future perspective. Therefore, drug repurposing was regarded as an effective avenue for COVID-19 treatment. Recently, molnupiravir is a prodrug antiviral medication that was approved in the United Kingdom in November 2021 for the treatment of COVID-19. On the other hand, PF-07321332 is an oral antiviral drug developed by Pfizer. For the treatment of COVID-19, the PF-07321332/ritonavir combination medication is used in Phase III studies and was marketed as Paxlovid. Herein, we represented the almost history of combating COVID-19 from repurposing to the recently available oral anti-SARS-CoV-2 candidates, as a new hope to end the current pandemic. Graphical

Multi-Phase In Silico Discovery of Potential SARS-CoV-2 RNA-Dependent RNA Polymerase Inhibitors among 3009 Clinical and FDA-Approved Related Drugs

Proceeding our prior studies of SARS-CoV-2, the inhibitory potential against SARS-CoV-2 RNA-dependent RNA polymerase (RdRp) has been investigated for a collection of 3009 clinical and FDA-approved drugs. A multi-phase in silico approach has been employed in this study. Initially, a molecular fingerprint experiment of Remdesivir (RTP), the co-crystallized ligand of the examined protein, revealed the most similar 150 compounds. Among them, 30 compounds were selected after a structure similarity experiment. Subsequently, the most similar 30 compounds were docked against SARS-CoV-2 RNA-dependent RNA polymerase (PDB ID: 7BV2). Aloin 359, Baicalin 456, Cefadroxil 1273, Sophoricoside 1459, Hyperoside 2109, and Vitexin 2286 exhibited the most precise binding modes, as well as the best binding energies. To confirm the obtained results, MD simulations experiments have been conducted for Hyperoside 2109, the natural flavonoid glycoside that exhibited the best docking scores, against RdRp (PDB ID: 7BV2) for 100 ns. The achieved results authenticated the correct binding of 2109, showing low energy and optimum dynamics. Our team presents these outcomes for scientists all over the world to advance in vitro and in vivo examinations against COVID-19 for the promising compounds.

Jusanin, a New Flavonoid from Artemisia commutata with an In Silico Inhibitory Potential against the SARS-CoV-2 Main Protease.

A new flavonoid, Jusanin, (1) has been isolated from the aerial parts of Artemisia commutata. The chemical structure of Jusanin has been elucidated using 1D, 2D NMR, and HR-Ms spectroscopic methods to be 5,2',4'-trihydroxy-6,7,5'-trimethoxyflavone. Being new in nature, the inhibition potential of 1 has been estimated against SARS-CoV-2 using different in silico techniques. Firstly, molecular similarity and fingerprint studies have been conducted for Jusanin against co-crystallized ligands of eight different SARS-CoV-2 essential proteins. The studies indicated the similarity between 1 and X77, the co-crystallized ligand SARS-CoV-2 main protease (PDB ID: 6W63). To confirm the obtained results, a DFT study was carried out and indicated the similarity of (total energy, HOMO, LUMO, gap energy, and dipole moment) between 1 and X77. Accordingly, molecular docking studies of 1 against the target enzyme have been achieved and showed that 1 bonded correctly in the protein's active site with a binding energy of -19.54 Kcal/mol. Additionally, in silico ADMET in addition to the toxicity evaluation of Jusanin against seven models have been preceded and indicated the general safety and the likeness of Jusanin to be a drug. Finally, molecular dynamics simulation studies were applied to investigate the dynamic behavior of the Mpro-Jusanin complex and confirmed the correct binding at 100 ns. In addition to 1, three other metabolites have been isolated and identified to be сapillartemisin A (2), methyl-3-[S-hydroxyprenyl]-cumarate (3), and ß-sitosterol (4).

Isolation and In Silico Anti-SARS-CoV-2 Papain-Like Protease Potentialities of Two Rare 2-Phenoxychromone Derivatives from Artemisia spp.

Two rare 2-phenoxychromone derivatives, 6-demethoxy-4`-O-capillarsine (1) and tenuflorin C (2), were isolated from the areal parts of Artemisia commutata and A. glauca, respectively, for the first time. Being rare in nature, the inhibition potentialities of 1 and 2 against SARS-CoV-2 was investigated using multistage in silico techniques. At first, molecular similarity and fingerprint studies were conducted for 1 and 2 against co-crystallized ligands of eight different COVID-19 enzymes. The carried-out studies indicated the similarity of 1 and 2 with TTT, the co-crystallized ligand of COVID-19 Papain-Like Protease (PLP), (PDB ID: 3E9S). Therefore, molecular docking studies of 1 and 2 against the PLP were carried out and revealed correct binding inside the active site exhibiting binding energies of -18.86 and -18.37 Kcal/mol, respectively. Further, in silico ADMET in addition to toxicity evaluation of 1 and 2 against seven models indicated the general safety and the likeness of 1 and 2 to be drugs. Lastly, to authenticate the binding and to investigate the thermodynamic characters, molecular dynamics (MD) simulation studies were conducted on 1 and PLP.

In Silico Exploration of Potential Natural Inhibitors against SARS-Cov-2 nsp10.

In continuation of our previous effort, different in silico selection methods were applied to 310 naturally isolated metabolites that exhibited antiviral potentialities before. The applied selection methods aimed to pick the most relevant inhibitor of SARS-CoV-2 nsp10. At first, a structural similarity study against the co-crystallized ligand, S-Adenosyl Methionine (SAM), of SARS-CoV-2 nonstructural protein (nsp10) (PDB ID: 6W4H) was carried out. The similarity analysis culled 30 candidates. Secondly, a fingerprint study against SAM preferred compounds 44, 48, 85, 102, 105, 182, 220, 221, 282, 284, 285, 301, and 302. The docking studies picked 48, 182, 220, 221, and 284. While the ADMET analysis expected the likeness of the five candidates to be drugs, the toxicity study preferred compounds 48 and 182. Finally, a density-functional theory (DFT) study suggested vidarabine (182) to be the most relevant SARS-Cov-2 nsp10 inhibitor.

In Silico Screening of Semi-Synthesized Compounds as Potential Inhibitors for SARS-CoV-2 Papain-like Protease: Pharmacophoric Features, Molecular Docking, ADMET, Toxicity and DFT Studies.

Papain-like protease is an essential enzyme in the proteolytic processing required for the replication of SARS-CoV-2. Accordingly, such an enzyme is an important target for the development of anti-SARS-CoV-2 agents which may reduce the mortality associated with outbreaks of SARS-CoV-2. A set of 69 semi-synthesized molecules that exhibited the structural features of SARS-CoV-2 papain-like protease inhibitors (PLPI) were docked against the coronavirus papain-like protease (PLpro) enzyme (PDB ID: (4OW0). Docking studies showed that derivatives 34 and 58 were better than the co-crystallized ligand while derivatives 17, 28, 31, 40, 41, 43, 47, 54, and 65 exhibited good binding modes and binding free energies. The pharmacokinetic profiling study was conducted according to the four principles of the Lipinski rules and excluded derivative 31. Furthermore, ADMET and toxicity studies showed that derivatives 28, 34, and 47 have the potential to be drugs and have been demonstrated as safe when assessed via seven toxicity models. Finally, comparing the molecular orbital energies and the molecular electrostatic potential maps of 28, 34, and 47 against the co-crystallized ligand in a DFT study indicated that 28 is the most promising candidate to interact with the target receptor (PLpro).

Comprehensive In Silico Screening of the Antiviral Potentialities of a New Humulene Glucoside from Asteriscus hierochunticus against SARS-CoV-2

Chromatographic fractionation of the methanolic extract of Asteriscus hierochunticus whole plant led to the identification of a new humulene glucoside (1). The chemical structure of the isolated compound was elucidated by IR, 1D, 2D NMR, and HRESIMS data analysis to be (-)-(2Z,6E,9E)8α-hydroxy-2,6,9-humulatrien-1(12)-olide. In this study, we report the in silico binding affinities of 1 against four different SARS-CoV-2 proteins (COVID-19 main protease (PDB ID: 6lu7), nonstructural protein (PDB ID: 6W4H), RNA-dependent RNA polymerase (PDB ID: 7BV2), and SARS-CoV-2 helicase (PDB ID: 5RMM)). The isolated compound showed excellent binding affinity values (ΔG) of −21.65, −20.05, −28.93, and −21.73 kcal/mol, respectively, against the target proteins compared to the cocrystallized ligands that exhibited ΔG values of −23.75, −17.65, −23.57, and −15.30 kcal/mol, respectively. Further in silico investigations of the isolated compound (1) for its ADMET and toxicity profiles revealed excellent drug likeliness. On the other hand, the results obtained from in vitro antitrypanosomal, antileishmanial, and antimalarial activities of (1) were not promising. [ABSTRACT FROM AUTHOR] Copyright of Journal of Chemistry is the property of Hindawi Limited and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Molecular Docking and Dynamics Simulation Revealed the Potential Inhibitory Activity of ACEIs Against SARS-CoV-2 Targeting the hACE2 Receptor.

The rapid and global spread of a new human coronavirus, Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) has produced an immediate urgency to discover promising targets for the treatment of COVID-19. Here, we consider drug repurposing as an attractive approach that can facilitate the drug discovery process by repurposing existing pharmaceuticals to treat illnesses other than their primary indications. We review current information concerning the global health issue of COVID-19 including promising approved drugs, e.g., human angiotensin-converting enzyme inhibitors (hACEIs). Besides, we describe computational approaches to be used in drug repurposing and highlight examples of in-silico studies of drug development efforts against SARS-CoV-2. Alacepril and lisinopril were found to interact with human angiotensin-converting enzyme 2 (hACE2), the host entranceway for SARS-CoV-2 spike protein, through exhibiting the most acceptable rmsd_refine values and the best binding affinity through forming a strong hydrogen bond with Asn90, which is assumed to be essential for the activity, as well as significant extra interactions with other receptor-binding residues. Furthermore, molecular dynamics (MD) simulations followed by calculation of the binding free energy were also carried out for the most promising two ligand-pocket complexes from docking studies (alacepril and lisinopril) to clarify some information on their thermodynamic and dynamic properties and confirm the docking results as well. These results we obtained probably provided an excellent lead candidate for the development of therapeutic drugs against COVID-19. Eventually, animal experiments and accurate clinical trials are needed to confirm the potential preventive and treatment effect of these compounds.

In Silico Studies of Some Isoflavonoids as Potential Candidates against COVID-19 Targeting Human ACE2 (hACE2) and Viral Main Protease (Mpro).

The Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) caused the "COVID-19" disease that has been declared by WHO as a global emergency. The pandemic, which emerged in China and widespread all over the world, has no specific treatment till now. The reported antiviral activities of isoflavonoids encouraged us to find out its in silico anti-SARS-CoV-2 activity. In this work, molecular docking studies were carried out to investigate the interaction of fifty-nine isoflavonoids against hACE2 and viral Mpro. Several other in silico studies including physicochemical properties, ADMET and toxicity have been preceded. The results revealed that the examined isoflavonoids bound perfectly the hACE-2 with free binding energies ranging from -24.02 to -39.33 kcal mol-1, compared to the co-crystallized ligand (-21.39 kcal mol-1). Furthermore, such compounds bound the Mpro with unique binding modes showing free binding energies ranging from -32.19 to -50.79 kcal mol-1, comparing to the co-crystallized ligand (binding energy = -62.84 kcal mol-1). Compounds 33 and 56 showed the most acceptable affinities against hACE2. Compounds 30 and 53 showed the best docking results against Mpro. In silico ADMET studies suggest that most compounds possess drug-likeness properties.

Comprehensive Virtual Screening of the Antiviral Potentialities of Marine Polycyclic Guanidine Alkaloids against SARS-CoV-2 (COVID-19).

The huge global expansion of the COVID-19 pandemic caused by the novel SARS-corona virus-2 is an extraordinary public health emergency. The unavailability of specific treatment against SARS-CoV-2 infection necessitates the focus of all scientists in this direction. The reported antiviral activities of guanidine alkaloids encouraged us to run a comprehensive in silico binding affinity of fifteen guanidine alkaloids against five different proteins of SARS-CoV-2, which we investigated. The investigated proteins are COVID-19 main protease (Mpro) (PDB ID: 6lu7), spike glycoprotein (PDB ID: 6VYB), nucleocapsid phosphoprotein (PDB ID: 6VYO), membrane glycoprotein (PDB ID: 6M17), and a non-structural protein (nsp10) (PDB ID: 6W4H). The binding energies for all tested compounds indicated promising binding affinities. A noticeable superiority for the pentacyclic alkaloids particularly, crambescidin 786 (5) and crambescidin 826 (13) has been observed. Compound 5 exhibited very good binding affinities against Mpro (ΔG = -8.05 kcal/mol), nucleocapsid phosphoprotein (ΔG = -6.49 kcal/mol), and nsp10 (ΔG = -9.06 kcal/mol). Compound 13 showed promising binding affinities against Mpro (ΔG = -7.99 kcal/mol), spike glycoproteins (ΔG = -6.95 kcal/mol), and nucleocapsid phosphoprotein (ΔG = -8.01 kcal/mol). Such promising activities might be attributed to the long ω-fatty acid chain, which may play a vital role in binding within the active sites. The correlation of c Log P with free binding energies has been calculated. Furthermore, the SAR of the active compounds has been clarified. The Absorption, Distribution, Metabolism, Excretion, and Toxicity (ADMET) studies were carried out in silico for the 15 compounds; most examined compounds showed optimal to good range levels of ADMET aqueous solubility, intestinal absorption and being unable to pass blood brain barrier (BBB), non-inhibitors of CYP2D6, non-hepatotoxic, and bind plasma protein with a percentage less than 90%. The toxicity of the tested compounds was screened in silico against five models (FDA rodent carcinogenicity, carcinogenic potency TD50, rat maximum tolerated dose, rat oral LD50, and rat chronic lowest observed adverse effect level (LOAEL)). All compounds showed expected low toxicity against the tested models. Molecular dynamic (MD) simulations were also carried out to confirm the stable binding interactions of the most promising compounds, 5 and 13, with their targets. In conclusion, the examined 15 alkaloids specially 5 and 13 showed promising docking, ADMET, toxicity and MD results which open the door for further investigations for them against SARS-CoV-2.