Synthesis and Virtual Screening of Pyrazolothiazole Conjugates as Promising SARS-CoV-2 Inhibitors

The current coronavirus outbreak has highlighted the significance of continuing to develop novel antiviral agents. The SARS-CoV-2 main protease (M-pro), essential for virus replication, has been recognized as a potential target for developing novel COVID-19 therapeutics. Herein, we report synthesizing a series of pyrazolothiazole conjugates and in silico molecular docking screening of their interactions with the COVID-19 protease 6LU7 protein. The new hybrids were obtained by condensing substituted pyrazole-4-carbaldehyde with N-phenyl-hydrazinecarbothioamide and subsequent refluxing with selected alpha-haloketones in a basic medium. The structures of the novel pyrazolothiazoles were fully verified by FTIR, H-1 NMR, C-13 NMR, and elemental analyses. Molecular docking and free energy analyses using the MM/GBSA approach revealed that 5 a-c and 7 a-c formed stable interactions within the protease 6LU7 pocket, thus, could be potential inhibitors of SARS-CoV-2.

Cathepsin inhibitors as potent inhibitors against SARS-CoV-2 main protease. In silico molecular screening and toxicity prediction

Since the emergence of the newly identified Coronavirus SARS-COV-2, no targeted therapeutic agents for COVID-19 treatment are available, and effective treatment options remain very limited. Successful crys-tallization of the SarS-CoV-2 main protease (Mpro, PDB-ID 6LU7) made possible the research on finding its potential inhibitors for the prevention of virus replication. To conduct molecular docking, we selected ten representatives of the Cathepsin inhibitors family as possible ligands with a high potential of binding the active site of SarS-CoV-2 main protease as a potential target. The results of molecular docking studies revealed that Ligand1 and Ligand2, with vina scores-8.8 and-8.7 kcal/mol for Mpro, respectively, were the most effective in binding. In silico prediction of physicochemical and toxicological behavior of assessed ligands approved the possibility of their use in clinical essays against SarS-COVID-19. © 2023, Palladin Institute of Biochemistry of the NASU. All rights reserved.

Inhibitory Potentials of Phytoconstituents of Phyllanthus amarus against Severe Acute Respiratory Syndrome-Corona Virus-2 Main Protease: A Computational Aided Approach

In 2019, a new strain of Coronavirus disease was identified in Wuhan, China. Specific therapies are unavailable and investigations regarding Coronavirus disease treatment are lacking. The present study aimed to assess bioactive compounds found in medicinal plant Phyllanthus amarus as potential Coronavirus disease main protease inhibitors, using a molecular docking study. Molecular docking was performed using Autodock 4.2. Coronavirus disease main protease was docked with several compounds, and docking was analysed by Autodock 4.2, Lopinavir was used as standard for comparison. The binding energies obtained from the docking of 6LU7 with native ligand, lopinavir, Phyllanthin, Hypophyllanthin, Hexanedioic acid, bis (2-ethylhexyl) ester, Benzeneethanamine,3,4-dimethoxy-n-((pentafluoro phenyl) methylene), Phenethylamine, 2-methoxy-alpha.-methyl-4,5-(methylenedioxy), Diisooctyl adipate, P-Tert-Octylresorcinol, 4-methyl-2,5-dimethoxy phenethylamine, 3-(2,4-dimethoxy-phenyl)-2-formylamino-propionic acid, ethyl ester, Rutin, Quercetin and Niranthin were-6.08,-4.44,-4.14,-2.32,-4.23,-4.07,-2.5,-4.66,-4.14,-3.38,-7.46,-6.28 and-4.62 kcal/mol, respectively. Therefore, lopinavir may represent potential treatment option and Rutin and Quercetin appeared to have the best potential to act as Coronavirus disease main protease inhibitors. Thus all the compounds have shown significant binding energy and potent inhibitory effect against Coronavirus disease main protease. However, further research is necessary to investigate their potential medicinal use.

Molecular docking analysis on 16 therapeutic ligands of Ocimum tenuiflorum L. (Tulasi) and their prospects in drug design for COVID-19

The PyRx software and Discovery studio were used in the present molecular docking studies of the 16 ligands of Ocimum tenuiflorum L., selected based on their high therapeutic potentials, viz., (E)-6-hydroxy-4,6-dimethylhept-3-en-2-one, Apigenin, Bieugenol, Cirsilineol, Cirsimaritin, β-Caryophyllene epoxide, Dehydrodieugenol B, Eugenol, Ferulaldehyde, Isothymonin, Isothymusin, Linalool, Luteolin, Ocimarin, Rosmarinic acid, and Thymol. Saquinavir was used as a positive control. The binding affinities of the 16 ligands to the main proteases of COVID-19 6LU7 and 6Y2E (critical for viral replication) and their ability to arrest the virus replication were recorded. The binding affinities of the ligands to 6LU7 and 6Y2E ranged from-4.3 and-4.7 kcal/mol (for (E)-6-hydroxy-4,6-dimethylhept-3-en-2-one) to-7.6 (for Rosmarinic acid to both target proteins). While the corresponding values for the control drug Saquinavir were-7.8 and-7.6 respectively. The Rosmarinic acid, in binding with both the proteases (-7.6 and-7.6 kcal/mol) showed six conventional hydrogen bonds, one carbon hydrogen bond (ASP 153 had one conventional hydrogen bond and one carbon hydrogen bond), one Pi-alkyl bond, one Pi-Pi stacked bond, eight van der waals bonds for 6LU7 protease;it formed three conventional hydrogen bonds, two Pi-alkyl bonds, one unfavourable donor – donor bond and 14 van der waals bonds with 6Y2E protease. The control drug – Saquinavir in binding with 6LU7 protease showed 12 van der waals, one alkyl, one Pi-alkyl, one Pi-cation, one Pi-stacked and four conventional hydrogen bonds, which indicates that it has less affinity when compared with Rosmarinic acid. Similarly, the control drug on binding with 6Y2E protease exhibited ten van der waals, four Pi-alkyl, one cation and three hydrogen bonds. The results are in conformity to similar other studies, and herald a promising scope for Rosmarinic acid as lead molecule in the drug discovery for COVID-19. © The authors.

Computational Prediction of Cassia angustifolia Compounds as a potential Drug Agents against Main Protease of SARS-nCov2

Background: In November-December 2019, a plethora of pneumonia like cases were reported in Wuhan, China. After some time, the causative agent of this ailment was identified and named as a novel coronavirus 2. This novel virus spread over the world with no time and declared as pandemic by WHO. To develop antiviral drugs, different clinically used drugs were used as a trial but went in vain. In the current study, we choose an herb with already known therapeutic effects to check its antiviral properties against this virus too. Methods: Cassia angustifolia is a well-known herb for pharmaceutical industries as its different compounds are already used in different medicines. Here we performed molecular docking of main compounds of Cassia angustifolia against the main protease of SARS-nCoV2 and were compared with different drugs that are already being used on commercial bases to obtain the lowest energy complex. Auto-Dock vina and its packages were used for molecular docking of SARS-nCov2. Results: Molecular docking of Cassia angustifolia compounds represent very promising binding energies complexes, e.g., Sennoside B gives -9.05kcal/mol and Aloe-Emodin give -4 Kcal/mol of energy against the main protease of coronavirus. In contrast, a couple of commercially used antiviral drugs were also evaluated against the selected protein of coronavirus e.g., Hydroxychloroquine and Ribavirin complexes appeared with -5.2 Kcal/mol and -6.3 Kcal/mol of energy respectively. Conclusion: Many compounds of Cassia angustifolia showed the promising energy complexes even better than the commercially used antiviral drugs e.g., Sennoside B which has the best energies against main protease of coronavirus. Further, in-vivo and in-vitro studies are needed to validate this hypothesis with advanced MD simulations and wet-lab experimentations.

An in silico study on inhibitability of Baloxavir marboxil, Baricitinib, Galidesivir, Nitazoxanide, and Oseltamivir against SARS-CoV-2

Baloxavir marboxil (D1), Baricitinib (D2), Galidesivir (D3), Nitazoxanide (D4), and Oseltamivir (D5) are well-known performing broad-spectrum activity against a variety of viruses, thus holding high potentiality towards SARS-CoV-2. Quantum properties were examined using density functional theory (DFT). The inhibitability of the drugs towards Angiotensin-converting enzyme 2 (ACE2) and SARS-CoV-2 main protease (6LU7) was evaluated by molecular docking simulation, while their bio-compatibility was justified by physicochemical properties obtained from QSARIS-based analysis in reference to Lipinski's rule of five. Quantum analysis suggests that the compounds are highly favourable for intermolecular interaction towards protein structures. Given ligand-ACE2 systems, the inhibitory effectiveness follows the order D3-ACE2?>?D4-ACE2?>?D2-ACE2?>?D5-ACE2?>?D1-ACE2;and the corresponding order for ligand-6LU7 systems is D2-6LU7?>?D4-6LU7?>?D3-6LU7?>?D5-6LU7?>?D1-6LU7. Galidesivir is predicted as the most effective inhibitor towards both targeted protein structures (DSaverage -13.1 kcal.mol-1) and the most bio-compatible molecule (Mass 264.9 amu;LogP -0.9;Polarisability 26.8 Å3). The theoretical screening suggests all drugs, especially Galidesivir (D3), promising for treatment of SARS-CoV-2 infection and encourages in-related clinical trials.

Methylxanthines as Potential Inhibitor of SARS-CoV-2: an In Silico Approach.

The aim of the present study was to test the binding affinity of methylxanthines (caffeine/theine, methylxanthine, theobromine, theophylline and xanthine) to three potential target proteins namely Spike protein (6LZG), main protease (6LU7) and nucleocapsid protein N-terminal RNA binding domain (6M3M) of SARS-CoV-2. Proteins and ligand were generated using AutoDock 1.5.6 software. Binding affinity of methylxanthines with SARS-CoV-2 target proteins was determined using Autodock Vina. MD simulation of the best interacting complexes was performed using GROMACS 2018.3 (in duplicate) and Desmond program version 2.0 (academic version) (in triplicate) to study the stabile interaction of protein-ligand complexes. Among the selected methylxanthines, theophylline showed the best binding affinity with all the three targets of SARS-CoV-2 (6LZG - 5.7 kcal mol-1, 6LU7 - 6.5 kcal mol-1, 6M3M - 5.8 kcal mol-1). MD simulation results of 100 ns (in triplicate) showed that theophylline is stable in the binding pockets of all the selected SARS-CoV-2 proteins. Moreover, methylxanthines are safer and less toxic as shown by high LD50 value with Protox II software as compared to drug chloroquine. This research supports the use of methylxanthines as a SARS-CoV-2 inhibitor. It also lays the groundwork for future studies and could aid in the development of a treatment for SARS-CoV-2 and related viral infections. Supplementary Information: The online version contains supplementary material available at 10.1007/s40495-021-00276-3.

Evaluation of SARS-CoV-2 inhibition of some compounds in CYMBOPOGON CITRATUS oil combining docking and molecular dynamics simulations

The visual screening and simulation methods were used to evaluate the inhibitory ability of 34 compounds in Cymbopogon citratus oil against SARS-CoV-2. We chose the best compound, SC22, with a DS of -12.80 Kcal. mol(-1) with a distance RMSD of 0.23. This was the most effective compound at inhibiting the viral protein 6LU7. For the protein ACE2 or an endemic host receptor, the docking ability of SC22 showed DS = -13.13 Kcal.mol(-1) and RMSD = 1.32 angstrom;SC10 docked in DS = -12.79 Kcal.mo1(-1) and RMSD = 0.91 angstrom;SC11 gave the docking values DS = -12.77 Kcal.moL(-1) and RMSD = 1.15 angstrom. SC26 showed DS = -12.76 Kcal.moL(-1) and RMSD = 1.44 angstrom;SC20 showed DS = -12.68 Kcal.moL(-1) and RMSD = 1.22 angstrom;the Cymbopogon cifratus oil involved the potential compounds for contributing to drug development. The compounds SC10, SC11, SC20, SC22 also tested and refined the druglikeness properties. The compound SC22 gives many druglikeness properties and is easy to carry out drug synthesis.

In silico identification of potential inhibitors against main protease of SARS-CoV-2 6LU7 from Andrographis panniculata via molecular docking, binding energy calculations and molecular dynamics simulation studies.

BACKGROUND: The ongoing global outbreak of new corona virus (SARS-CoV-2) has been recognized as global public health concern since it causes high morbidity and mortality every day. Due to the rapid spreading and re-emerging, we need to find a potent drug against SARS-CoV-2. Synthetic drugs, such as hydroxychloroquine, remdisivir have paid more attention and the effects of these drugs are still under investigation, due to their severe side effects. Therefore, the aim of the present study was performed to identify the potential inhibitor against main protease SARS-CoV-2 6LU7. OBJECTIVE: In this study, RO5, ADME properties, molecular dynamic simulations and free binding energy prediction were mainly investigated. RESULTS: The molecular docking study findings revealed that andrographolide had higher binding affinity among the selected natural diterpenoids compared to co-crystal native ligand inhibitor N3. The persistent inhibition of Ki for diterpenoids was analogous. Furthermore, the simulations of molecular dynamics and free binding energy findings have shown that andrographolide possesses a large amount of dynamic properties such as stability, flexibility and binding energy. CONCLUSION: In conclusion, findings of the current study suggest that selected diterpenoids were predicted to be the significant phytonutrient-based inhibitor against SARS-CoV-2 6LU7 (Mpro). However, preclinical and clinical trials are needed for the further scientific validation before use.

Discovery of Potent SARS-CoV-2 Inhibitors from Approved Antiviral Drugs via Docking and Virtual Screening.

BACKGROUND: Coronavirus Disease 2019 (COVID-19) pandemic continues to threaten patients, societies and healthcare systems around the world. There is an urgent need to search for possible medications. OBJECTIVE: This article intends to use virtual screening and molecular docking methods to find potential inhibitors from existing drugs that can respond to COVID-19. METHODS: To take part in the current research investigation and to define a potential target drug that may protect the world from the pandemic of corona disease, a virtual screening study of 129 approved drugs was carried out which showed that their metabolic characteristics, dosages used, potential efficacy and side effects are clear as they have been approved for treating existing infections. Especially 12 drugs against chronic hepatitis B virus, 37 against chronic hepatitis C virus, 37 against human immunodeficiency virus, 14 anti-herpesvirus, 11 anti-influenza, and 18 other drugs currently on the market were considered for this study. These drugs were then evaluated using virtual screening and molecular docking studies on the active site of the (SARS-CoV-2) main protease (6lu7). Once the efficacy of the drug is determined, it can be approved for its in vitro and in vivo activity against the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), which can be beneficial for the rapid clinical treatment of patients. These drugs were considered potentially effective against SARS-CoV-2 and those with high molecular docking scores were proposed as novel candidates for repurposing. The N3 inhibitor cocrystallized with protease (6lu7) and the anti-HIV protease inhibitor Lopinavir were used as standards for comparison. RESULTS: The results suggest the effectiveness of Beclabuvir, Nilotinib, Tirilazad, Trametinib and Glecaprevir as potent drugs against SARS-CoV-2 since they tightly bind to its main protease. CONCLUSION: These promising drugs can inhibit the replication of the virus; hence, the repurposing of these compounds is suggested for the treatment of COVID-19. No toxicity measurements are required for these drugs since they were previously tested prior to their approval by the FDA. However, the assessment of these potential inhibitors as clinical drugs requires further in vivo tests of these drugs.

Computation screening and molecular docking of FDA approved viral protease inhibitors as a potential drug against COVID-19.

AIM: This study demonstrated potent inhibitors against COVID-19 using the molecular docking approach of FDA approved viral antiprotease drugs. BACKGROUND: COVID-19 has now spread throughout world. There is a serious need to find potential therapeutic agents. The 3C-like protease (Mpro/6LU7) is an attractive molecular target for rational anti-CoV drugs. METHODS: The tertiary structure of COVID-19 Mpro was obtained from a protein data bank repository, and molecular docking screening was performed by Molegro Virtual Docker, ver. 6, with a grid resolution of 0.30 Å. Docking scores (DOS) are representative of calculated ligand-receptor (protein) interaction energy; therefore, more negative scores mean better binding tendency. Another docking study was then applied on each of the selected drugs with the best ligands separately and using a more accurate RMSD algorithm. RESULTS: The docking of COVID-19 major protease (6LU7) with 17 selected drugs resulted in four FDA approved viral antiprotease drugs (Temoporfin, Simeprevir, Cobicistat, Ritonavir) showing the best docking scores. Among these 4 compounds, Temoporfin exhibited the best DOS (-202.88) and the best screened ligand with COVID-19 Mpro, followed by Simeprevir (-201.66), Cobicistat (-187.75), and Ritonavir (-186.66). As the best screened ligand, Temoporfin could target the Mpro with 20 different conformations, while Simeprevir, Cobicistat, and Ritonavir make 14, 10, and 10 potential conformations at the binding site, respectively. CONCLUSION: The findings showed that the four selected FDA approved drugs can be potent inhibitors against COVID-19; among them, Temoporfin may be more potent for the treatment of the disease. Based on the findings, it is recommended that in-vitro and in-vivo evaluations be conducted to determine the effectiveness of these drugs against COVID-19.

The coronavirus disease 2019 main protease inhibitor from Andrographis paniculata (Burm. f) Ness.

The coronavirus disease 2019 (COVID-19) pandemic has attracted worldwide attention. Andrographis paniculata (Burm. f) Ness (AP) is naturally used to treat various diseases, including infectious diseases. Its Andrographolide has been clinically observed for anti-HIV and has also in silico tested for COVID-19 main protease inhibitors. Meanwhile, the AP phytochemicals content also provides insight into the molecular structures diversity for the bioactive discovery. This study aims to find COVID-19 main protease inhibitor from AP by the molecular docking method and determine the toxicity profile of the compounds. The results obtained two compounds consisting of flavonoid glycosides 5,4'-dihydroxy-7-O-ß -D-pyran-glycuronate butyl ester and andrographolide glycoside 3-O-ß-D-glucopyranosyl-andrographolide have lower free binding energy and highest similarity in types of interaction with amino acid residues compared to its co-crystal ligands (6LU7) and Indinavir or Remdesivir. The toxicity prediction of the compounds also reveals their safety. These results confirm the probability of using AP phytochemical compounds as COVID-19 main protease inhibitors, although further research must be carried out.

Synthesis, characterization and computational study on potential inhibitory action of novel azo imidazole derivatives against COVID-19 main protease (Mpro: 6LU7).

A series of six novel imidazole anchored azo-imidazole derivatives (L1-L6) have been prepared by the simple condensation reaction of azo-coupled ortho-vaniline precursor with amino functionalised imidazole derivative and the synthesized derivatives (L1-L6) have been characterized by different analytical and spectroscopic techniques. Molecular docking studies were carried out to ascertain the inhibitory action of studied ligands (L1-L6) against the Main Protease (6LU7) of novel coronavirus (COVID-19). The result of the docking of L1-L6 showed a significant inhibitory action against the Main protease (Mpro) of SARS-CoV-2 and the binding energy (ΔG) values of the ligands (L1-L6) against the protein 6LU7 have found to be -7.7 Kcal/mole (L1), -7.4 Kcal/mole (L2), -6.7 Kcal/mole (L3), -7.9 Kcal/mole (L4), -8.1 Kcal/mole (L5) and -7.9 Kcal/mole (L6). Pharmacokinetic properties (ADME) of the ligands (L1-L6) have also been studied.

Evaluation of the Inhibitory Activities of COVID-19 of Melaleuca cajuputi Oil Using Docking Simulation.

GC-MS was applied to identify 24 main substances in Melaleuca cajuputi essential oil (TA) extracted from fresh cajeput leaves through steam distilling. The inhibitory capability of active compounds in the TA from Thua Thien Hue, Vietnam over the Angiotensin-Converting Enzyme 2 (ACE2) protein in human body - the host receptor for SARS-CoV-2 and the main protease (PDB6LU7) of the SARS-CoV-2 using docking simulation has been studied herein. The results indicate that the ACE2 and PDB6LU7 proteins were strongly inhibited by 10 out of 24 compounds accounting for 70.9% in the TA. The most powerful anticoronavirus activity is expressed in the order: Terpineol (TA2) ≈ Guaiol (TA5) ≈ Linalool (TA19) > Cineol (TA1) > ß-Selinenol (TA3) > α-Eudesmol (TA4) > γ-Eudesmol (TA7). Interestingly, the synergistic interactions of these 10 substances of the TA exhibit excellent inhibition into the ACE2 and PDB6LU7 proteins. The docking results orient that the natural Melaleuca cajuputi essential oil is considered as a valuable resource for preventing SARS-CoV-2 invasion into human body.

Statins and the COVID-19 main protease: in silico evidence on direct interaction.

INTRODUCTION: No proven drug and no immunisation are yet available for COVID-19 disease. The SARS-CoV-2 main protease (Mpro), a key coronavirus enzyme, which is a potential drug target, has been successfully crystallised. There is evidence suggesting that statins exert anti-viral activity and may block the infectivity of enveloped viruses. The aim of this study was to assess whether statins are potential COVID-19 Mpro inhibitors, using a molecular docking study. MATERIAL AND METHODS: Molecular docking was performed using AutoDock/Vina, a computational docking program. SARS-CoV-2 Mpro was docked with all statins, while antiviral and antiretroviral drugs - favipiravir, nelfinavir, and lopinavir - were used as standards for comparison. RESULTS: The binding energies obtained from the docking of 6LU7 with native ligand favipiravir, nelfinavir, lopinavir, simvastatin, rosuvastatin, pravastatin, pitavastatin, lovastatin, fluvastatin, and atorvastatin were -6.8, -5.8, -7.9, -7.9, -7.0, -7.7, -6.6, -8.2, -7.4, -7.7, and -6.8 kcal/mol, respectively. The number of hydrogen bonds between statins and amino acid residues of Mpro were 7, 4, and 3 for rosuvastatin, pravastatin, and atorvastatin, respectively, while other statins had two hydrogen bonds. CONCLUSIONS: These results indicate, based upon the binding energy of pitavastatin, rosuvastatin, lovastatin, and fluvastatin, that statins could be efficient SARS-CoV-2 Mpro inhibitors. This is supported by the fact that the effects of some statins, especially pitavastatin, have a binding energy that is even greater than that of protease or polymerase inhibitors. However, further research is necessary to investigate their potential use as drugs for COVID-19.