SARS CoV-2 Main Protease Inhibitors Research Articles

PBPK Modeling of PAXLOVIDTM: Incorporating Rotamer Conversion Kinetics to Advanced Dissolution and Absorption Model

PAXLOVID™ is a combination medicine of nirmatrelvir tablets co-packaged with ritonavir tablets. Nirmatrelvir is a peptidomimetic inhibitor of SARS-CoV2 main protease (Mpro), developed for the treatment of COVID-19. Ritonavir is co-administered as a pharmacokinetics (PK) enhancer to inhibit CYP3A mediated metabolism increasing exposures of nirmatrelvir. In the solid form, nirmatrelvir exists in a stable single conformational state (ANTI form). However, nirmatrelvir exhibits atropisomerism in solution whereby upon dissolution the ANTI rotational isomer reversibly converts to another conformation state (SYN form). Nirmatrelvir rotamer conversion follows pseudo first order kinetics with a conversion half-life of approximately 15 min in aqueous solutions, which is on a similar time scale of diffusion mediated dissolution from the solid form. In vitro dissolution studies further indicated that rotamer conversion is one of the processes controlling nirmatrelvir dissolution. It was hypothesized that rotamer conversion kinetics would affect oral absorption of nirmatrelvir in vivo. Consequently, a physiologically based pharmacokinetic (PBPK) model for Paxlovid was developed in Simcyp™ using the advanced dissolution, absorption, and metabolism model (ADAM) by incorporating rotamer conversion kinetics to achieve a more mechanistic description of nirmatrelvir oral absorption. The results demonstrate that the established absorption model with rotamer kinetics adequately described observed clinical data from various nirmatrelvir doses, dosage forms, and dosing regimens. The predicted vs. observed AUCinf and Cmax ratios were within 2-fold. The model has been internally used to inform clinical studies and dose recommendations for pediatrics.

Design, synthesis, and biological evaluation of indole-2-carboxamides as SARS CoV-2 main protease inhibitors

Using a repurposing approach, a series of previously reported antiproliferative indole-based carboxamides (9–23) were reassessed for their anti-SARS-CoV-2 viral activity as main protease (SARS-CoV-2 Mpro) inhibitors. The structure of the indole-based carboxamides was validated by comparing the acquired data to previously report physicochemical and NMR spectroscopy data. The anti-SARS-CoV-2 activity of the synthesised compounds was tested in Vero-E6 cells using SARS-CoV-2 (NRC-03-nhCoV) virus. MTT cytotoxicity assay results demonstrated that compounds 9–23 had CC50 (50% cytotoxicity concentration) values ranging from 325.60 to 578.50 μM and safety indices ranging from 21.40 to 99.60. Most of the compounds examined significantly inhibited NRC-03-nhCoV virus replication, with IC50 values ranging from 3.60 μM to 15.20 μM, with compounds 11, 19, and 20 having the most potent anti-SARS-COV-2 activity. The inhibitory effect of compounds 11, 13, 14, 19 and 20 against SARS-CoV-2 Mpro was investigated. The findings of this test were consistent with the anti-SARS CoV-2 experiment. Inflammatory cytokine tests revealed that compounds 11, 19 and 20 have antiviral effectiveness against SARS-CoV-2 and can reduce hyper inflammation. Finally, docking studies of the novel compounds in the SARS CoV-2-Mpro active site revealed a good match.

Virtual Screening Approach in Identification of Bioactive Lignans from Medicinal Plants as Potential Lead Compounds against Main Protease of SARS-CoV-2 COVID-19

Background Lignans are an important class of phytochemicals obtained from various plant species and show structural similarity. They possessed a core scaffold formed by two or more phenylpropanoid units. Lignans have many of biological and antiviral activities reported in recent years. Objectives The main objective of the present study is to investigate the bioactive lignans against the molecular target of a new strain of coronavirus.Methods Using molecular docking studies we have investigated important lignans mainly niranthin diphyllin phillygenin and bicyclol against the main protease enzyme of coronavirus. Nelfinavir was used as a standard drug to compare binding energies. The main protease enzyme of coronavirus was docked with selected compounds using PyRx 0.8 and docking was analyzed by Biovia Discovery Studio 2019.Results The binding energies of nelfinavir niranthin diphyllin phillygenin and bicyclol with molecular target were calculated using molecular docking studies and it was found to be -8.3 -6.1 -8.1 -6.6 -6.5 respectively.Conclusion From the binding energy calculations it was concluded that nelfinavir represents a potential treatment option whereas niranthin diphyllin phillygenin and bicyclol possessed the best inhibitors of SARSCoV-2 main protease.

Euphorbia neriifolia L. phytochemical lead compounds discovered using pharmacoinformatic methods as possible SARS CoV-2 main protease inhibitors

Euphorbia neriifolia L. phytochemical lead compounds discovered using pharmacoinformatic methods as possible SARS CoV-2 main protease inhibitors

IN-SILICO MOLECULAR DOCKING OF DICHLOLOROFLAVAN FROM ZINGIER OFFICINALE AND ALLICIN FROM ALLIUM SATIVUM AGAINST MPRO A DRUG TARGET OF SARS COV-2

From decades, viral diseases including emerging and chronic viral infections are increasing worldwide health concern. Corona virus, SARS COV-2, is a new strain identified in 2019 caused Covid-19, in Wuhan, China has caused more than 5,304,772 infections and ~342,029 deaths worldwide over 203 countries, and the numbers are increasing exponentially from time to time. Since no specific treatment and diagnosis are available for COVID-19, discovery of new antiviral agents have become the most urgent need than in past, especially from natural sources. Hence, our present study is aimed to investigate bioactive molecules from Zingiber officinale (ginger) and Allium sativum (garlic) as potential SARS COV-2 main protease inhibitors, using a molecular docking by Auto dock 4.2, with the Lamarckian Genetic Algorithm, to analyze the probability of docking. SARS COV-2 main protease was docked with five selected compounds (zingerone, gingerol, paradol, dichloro flavin (ginger), and allicin (garlic), and were analyzed by Auto dock 4.2, PyMol version 1.7.4.5. Chloroquine and hydroxy chloroquine were used as standards for comparison. The binding energies obtained from the docking of Covid-19 main protease with biological ligand; zingerone, gingerol, paradol, dichloro flavin, and allicin were -5.31, -4.73, -5.51, -6.05, -3.74 kcal/mol, while, standard drugs such as hydroxy chloroquine and chloroquine possess binding energies of -4.88 and -5.25 kcal/mol respectively. It indicates that, zingerone, paradol and dichloloroflavan show more binding energy than chloroquine and hydroxy chloroquine, whereas, gingerol and allicin exhibited lesser binding energy. Comparing these five molecules, dichloroflavan and paradol from ginger shows highest affinity and binding sites for target protein.

Identification of Anti-HIV/Migraine Drugs as Potential Inhibitors of SARS-Cov2 Main Protease Using in Silico Assessments

Background: The acute respiratory syndrome named “COVID-19” is caused by a novel coronavirus called Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2). Lack of specific antiviral drugs or proper vaccination has led to the development of new therapeutic methods against this virus. Objective The Mpro 3Clpro is the main protease of the SARS-CoV-2 which plays an important role in replication and transcription of the virus. Therefore, targeting this enzyme is a valuable approach for drug development. Methods: In the present study, the structural properties of 69 anti-migraine and 212 anti-HIV drugs were first obtained from Drug Bank database. To select the appropriate drugs for the enzyme inhibition, the AutoDock Vina software was used. The molecular dynamics (MD) simulation method was applied for better recognition of the structural changes. Results: We identified Rimegepant (PubChem ID: 51049968), Dihydroergotamine (PubChem ID: 10531) and Ergotamine (PubChem ID: 8223) as potential inhibitors of Mpro 3Clpro. These complexes were equilibrated after 70 ns. Conclusion: Among these compounds, the anti-migraine drug “Rimegepant” showed the highest affinity for binding to the Mpro 3Clpro (-60.8 kJ/mol). This study provides enough evidence for further accomplishment of the identified compounds in the development of effective therapeutics methods against COVID-19.

From genomes to molecular dynamics – A bottom up approach in extrication of SARS CoV-2 main protease inhibitors

The recent pandemic Coronavirus disease-19 outbreak had traumatized global countries since its origin in late December 2019. Though the virus originated in China, it has spread rapidly across the world due its firmly established community transmission. To successfully tackle the spread and further infection, there needs a clear multidimensional understanding of the molecular mechanisms. Henceforth, 942 viral genome sequences were analysed to predict the core genomes crucial in virus life cycle. Additionally, 35 small interfering RNA transcripts were predicted that can target specifically the viral core proteins and reduce pathogenesis. The crystal structure of Covid-19 main protease-6LU7 was chosen as an attractive target due to the factors that there were fewer mutations and whose structure had significant identity to the annotated protein sequence of the core genome. Drug repurposing of both recruiting and non recruiting drugs was carried out through molecular docking procedures to recognize bitolterol as a good inhibitor of Covid-19 protease. The study was extended further to screen antiviral phytocompounds through quantitative structure activity relationship and molecular docking to identify davidigenin, from licorice as the best novel lead with good interactions and binding energy. The docking of the best compounds in all three categories was validated with molecular dynamics simulations which implied stable binding of the drug and lead molecule. Though the studies need clinical evaluations, the results are suggestive of curbing the pandemic.

Computer aided identification of potential SARS CoV-2 main protease inhibitors from diterpenoids and biflavonoids of Torreya nucifera leaves

SARS CoV-2 is the causative agent of the pandemic disease COVID-19. There is an urgent need for effective drugs or vaccines which can effectively combat this outbreak. The main protease (Mpro), a key component for the SARS CoV-2 replication, is considered to be one of the important drug targets for developing anti-COVID-19 drugs. This SARS CoV-2 Mpro/cysteine protease has high sequence similarity with the same protease from SARS CoV-1. Previously, it has been shown experimentally that eight diterpenoids and four biflavonoids derived from the leaf of Torreya nucifera show inhibitory effect on the cleavage/catalytic activity of the SARS CoV-1 Mpro. But whether these phytochemicals exhibit any inhibitory effect on SARS CoV-2 Mpro is unclear. To understand this fact, here, we have adopted various in-silico approaches. Diterpenoids and biflavonoids those qualified pharmacological test (hinokiol, amentoflavone, bilobetin and ginkgetin) and two well-known Mpro inhibitors (N3 and lopinavir) were subjected for molecular docking studies. Only three biflavonoids (amentoflavone, bilobetin and ginkgetin) were selected by comparing their binding affinities with N3 and lopinavir. They interacted with two most important catalytic residues of Mpro (His41 and Cys145). Molecular dynamics studies further revealed that these three Mpro-biflavonoid complexes are highly stable and share a similar degree of compactness. Besides, these complexes experience less conformational fluctuations and more expansion than Mpro-N3 and/or Mpro-lopinavir complex. MM-GBSA and H-bond analysis further corroborated these findings. Altogether, our study suggested that these three biflavonoids could possibly inhibit the proteolytic/catalytic activity of SARS CoV-2 Mpro and might be useful for COVID-19 treatment. Communicated by Ramaswamy H. Sarma

Potential therapeutic use of corticosteroids as SARS CoV-2 main protease inhibitors: a computational study

The outbreak of COVID-19, caused by severe acute respiratory syndrome coronavirus 2 (SARS CoV-2), represents a pandemic threat to global public health. To date, ∼530,000 people died of this disease worldwide. Presently, researchers/clinicians are adopting the drug repurposing strategy to combat this disease. It has also been observed that some repurposed anti-viral drugs may serve as potent inhibitors of SARS CoV-2 Mpro, a key component of viral replication. Apart from these anti-viral drugs, recently dexamethasone (an important corticosteroid) is effectively used to treat COVID-19 patients. However, the mechanism behind the mode of its action is not so clear. Additionally, the effect of other well-known corticosteroids to control this disease by inhibiting the proteolytic activity of Mpro is ambiguous. In this study, we have adopted computational approaches to understand these aspects. Six well-known corticosteroids (cortisone, hydrocortisone, prednisolone, methylprednisolone, betamethasone and dexamethasone) and two repurposed drugs (darunavir and lopinavir) against COVID-19 were subjected for molecular docking studies. Two of them (betamethasone and dexamethasone) were selected by comparing their binding affinities with selected repurposed drugs toward Mpro. Betamethasone and dexamethasone interacted with both the catalytic residues of Mpro (His41 and Cys145). Molecular dynamics studies further revealed that these two Mpro-corticosteroid complexes are more stable, experience less conformational fluctuations and more compact than Mpro-darunavir/lopinavir complexes. These findings were additionally validated by MM-GBSA analysis. This study provides corroboration for execution of anti-COVID-19 activity of dexamethasone. Our study also emphasizes on the use of another important corticosteroid (betamethasone) as potential therapeutic agent for COVID-19 treatment.

Structural basis for the inhibition of SARS-CoV2 main protease by Indian medicinal plant-derived antiviral compounds

A novel coronavirus (SARS-CoV2) has caused a major outbreak in humans around the globe, and it became a severe threat to human healthcare than all other infectious diseases. Researchers were urged to discover and test various approaches to control and prevent such a deadly disease. Considering the emergency and necessity, we screened reported antiviral compounds present in the traditional Indian medicinal plants for the inhibition of SARS-CoV2 main protease. In this study, we used molecular docking to screen 41 reported antiviral compounds that exist in Indian medicinal plants and shown amentoflavone from the plant Torreyanucifera with a higher docking score. Furthermore, we performed a 40 ns atomic molecular dynamics simulation and free binding energy calculations to explore the stability of the top five protein–ligand complexes. Through the article, we insist that the amentoflavone, hypericin and Torvoside H from the traditional Indian medicinal plants may be used as a potential inhibitor of SARS-CoV2 main protease and further biochemical experiments could shed light on understanding the mechanism of inhibition by these plant-derived antiviral compounds. Communicated by Ramaswamy H. Sarma

Identification of alkaloids from Justicia adhatoda as potent SARS CoV-2 main protease inhibitors: An in silico perspective

The COVID-19 pandemic, caused by SARS CoV-2, is responsible for millions of death worldwide. No approved/proper therapeutics is currently available which can effectively combat this outbreak. Several attempts have been undertaken in the search of effective drugs to control the spread of SARS CoV-2 infection. The main protease (Mpro), key component for the cleavage of the viral polyprotein, is considered to be one of the important drug targets for treating COVID-19. Various phytochemicals, including polyphenols and alkaloids, have been proposed as potent inhibitors of Mpro. The alkaloids from leaf extracts of Justicia adhatoda have also been reported to possess anti-viral activity. But whether these alkaloids exhibit any inhibitory effect on SARS CoV-2 Mpro is far from clear. To explore this in detail, we have adopted computational approaches. Justicia adhatoda alkaloids possessing proper drug-likeness properties and two anti-HIV drugs (lopinavir and darunavir; having binding affinity -7.3 to -7.4 kcal/mol) were docked against SARS CoV-2 Mpro to study their binding properties. Only one alkaloid (anisotine) had interaction with both the catalytic residues (His41 and Cys145) of Mpro and exhibited good binding affinity (-7.9 kcal/mol). Molecular dynamic simulations (100 ns) revealed that Mpro-anisotine complex is more stable, conformationally less fluctuated; slightly less compact and marginally expanded than Mpro-darunavir/lopinavir complex. Even the number of intermolecular H-bonds and MM-GBSA analysis suggested that anisotine is a more potent Mpro inhibitor than the two previously recommended antiviral drugs (lopinavir and darunavir) and may evolve as a promising anti-COVID-19 drug if proven in animal experiments and on patients.

BANΔIT: B'-Factor Analysis for Drug Design and Structural Biology.

The analysis of B‐factor profiles from X‐ray protein structures can be utilized for structure‐based drug design since protein mobility changes have been associated with the quality of protein‐ligand interactions. With the BANΔIT (B’‐factor analysis and ΔB’ interpretation toolkit), we have developed a JavaScript‐based browser application that provides a graphical user interface for the normalization and analysis of B’‐factor profiles. To emphasize the usability for rational drug design applications, we have analyzed a selection of crystallographic protein‐ligand complexes and have given exemplary conclusions for further drug optimization including the development of a B’‐factor‐supported pharmacophore model for SARS CoV‐2 main protease inhibitors. BANΔIT is available online at https://bandit.uni‐mainz.de. The source code can be downloaded from https://github.com/FBarthels/BANDIT.

Identification of polyphenols from Broussonetia papyrifera as SARS CoV-2 main protease inhibitors using in silico docking and molecular dynamics simulation approaches

The current COVID-19 pandemic is caused by SARS CoV-2. To date, ∼463,000 people died worldwide due to this disease. Several attempts have been taken in search of effective drugs to control the spread of SARS CoV-2 infection. The main protease (Mpro) from SARS CoV-2 plays a vital role in viral replication and thus serves as an important drug target. This Mpro shares a high degree of sequence similarity (>96%) with the same protease from SARS CoV-1 and MERS. It was already reported that Broussonetia papyrifera polyphenols efficiently inhibit the catalytic activity of SARS CoV-1 and MERS Mpro. But whether these polyphenols exhibit any inhibitory effect on SARS CoV-2 Mpro is far from clear. To understand this fact, here we have adopted computational approaches. Polyphenols having proper drug-likeness properties and two repurposed drugs (lopinavir and darunavir; having binding affinity −7.3 to −7.4 kcal/mol) were docked against SARS CoV-2 Mpro to study their binding properties. Only six polyphenols (broussochalcone A, papyriflavonol A, 3'-(3-methylbut-2-enyl)-3',4',7-trihydroxyflavane, broussoflavan A, kazinol F and kazinol J) had interaction with both the catalytic residues (His41 and Cys145) of Mpro and exhibited good binding affinity (−7.6 to −8.2 kcal/mol). Molecular dynamic simulations (100 ns) revealed that all Mpro-polyphenol complexes are more stable, conformationally less fluctuated; slightly less compact and marginally expanded than Mpro-darunavir/lopinavir complex. Even the number of intermolecular H-bond and MM-GBSA analysis suggested that these six polyphenols are more potent Mpro inhibitors than the two repurposed drugs (lopinavir and darunavir) and may serve as promising anti-COVID-19 drugs.

Identification of potential natural inhibitors of SARS-CoV2 main protease by molecular docking and simulation studies

Coronaviruses are contagious pathogens primarily responsible for respiratory and intestinal infections. Research efforts to develop antiviral agents against coronavirus demonstrated the main protease (Mpro) protein may represent effective drug target. X-ray crystallographic structure of the SARS-CoV2 Mpro protein demonstrated the significance of Glu166, Cys141, and His41 residues involved in protein dimerization and its catalytic function. We performed in silico screening of compounds from Curcuma longa L. (Zingiberaceae family) against Mpro protein inhibition. Employing a combination of molecular docking, scoring functions, and molecular dynamics simulations, 267 compounds were screened by docking on Mpro crystallographic structure. Docking score and interaction profile analysis exhibited strong binding on the Mpro catalytic domain with compounds C1 (1E,6E)-1,2,6,7-tetrahydroxy-1,7-bis(4-hydroxy-3-methoxyphenyl)hepta-1,6-diene-3,5-dione) and C2 (4Z,6E)‐1,5‐dihydroxy‐1,7‐bis(4‐hydroxyphenyl)hepta‐4,6‐dien‐3‐one as lead agents. Compound C1 and C2 showed minimum binding score (–9.08 and –8.07 kcal/mole) against Mpro protein in comparison to shikonin and lopinavir (≈ −5.4 kcal/mole) a standard Mpro inhibitor. Furthermore, principal component analysis, free energy landscape and protein-ligand energy calculation studies revealed that these two compounds strongly bind to the catalytic core of the Mpro protein with higher efficacy than lopinavir, a standard antiretroviral of the protease inhibitor class. Taken together, this structure based optimization has provided lead on two natural Mpro inhibitors for further testing and development as therapeutics against human coronavirus. Communicated by Ramaswamy H. Sarma