In Silico Comparative Analysis of Ivermectin and Nirmatrelvir Inhibitors Interacting with the SARS-CoV-2 Main Protease.

Exploring therapeutic options is crucial in the ongoing COVID-19 pandemic caused by SARS-CoV-2. Nirmatrelvir, which is a potent inhibitor that targets the SARS-CoV-2 Mpro, shows promise as an antiviral treatment. Additionally, Ivermectin, which is a broad-spectrum antiparasitic drug, has demonstrated effectiveness against the virus in laboratory settings. However, its clinical implications are still debated. Using computational methods, such as molecular docking and 100 ns molecular dynamics simulations, we investigated how Nirmatrelvir and Ivermectin interacted with SARS-CoV-2 Mpro(A). Calculations using density functional theory were instrumental in elucidating the behavior of isolated molecules, primarily by analyzing the frontier molecular orbitals. Our analysis revealed distinct binding patterns: Nirmatrelvir formed strong interactions with amino acids, like MET49, MET165, HIS41, HIS163, HIS164, PHE140, CYS145, GLU166, and ASN142, showing stable binding, with a root-mean-square deviation (RMSD) of around 2.0 Å. On the other hand, Ivermectin interacted with THR237, THR239, LEU271, LEU272, and LEU287, displaying an RMSD of 1.87 Å, indicating enduring interactions. Both ligands stabilized Mpro(A), with Ivermectin showing stability and persistent interactions despite forming fewer hydrogen bonds. These findings offer detailed insights into how Nirmatrelvir and Ivermectin bind to the SARS-CoV-2 main protease, providing valuable information for potential therapeutic strategies against COVID-19.

Harnessing Brazilian biodiversity database: identification of flavonoids as potential inhibitors of SARS-CoV-2 main protease using computational approaches and all-atom molecular dynamics simulation.

SARS-CoV-2 (Severe Acute Respiratory Syndrome Coronavirus 2) is the etiological agent responsible for the global outbreak of COVID-19 (Coronavirus Disease 2019). The main protease of SARS-CoV-2, Mpro, is a key enzyme that plays a vital role in mediating viral replication and transcription. In this study, a comprehensive computational approach was employed to investigate the binding affinity, selectivity, and stability of natural product candidates as potential new antivirals acting on the viral polyprotein processing mediated by SARS-CoV-2 Mpro. A library of 288 flavonoids extracted from Brazilian biodiversity was screened to select potential Mpro inhibitors. An initial filter based on Lipinski's rule of five was applied, and 204 compounds that did not violate any of the Lipinski rules were selected. The compounds were then docked into the active site of Mpro using the GOLD program, and the poses were subsequently re-scored using MM-GBSA (Molecular Mechanics Generalized Born Surface Area) binding free energy calculations performed by AmberTools23. The top five flavonoids with the best MM-GBSA binding free energy values were selected for analysis of their interactions with the active site residues of the protein. Next, we conducted a toxicity and drug-likeness analysis, and non-toxic compounds were subjected to molecular dynamics simulation and free energy calculation using the MM-PBSA (Molecular Mechanics Poisson-Boltzmann Surface Area) method. It was observed that the five selected flavonoids had lower MM-GBSA binding free energy with Mpro than the co-crystal ligand. Furthermore, these compounds also formed hydrogen bonds with two important residues, Cys145 and Glu166, in the active site of Mpro. Two compounds that passed the drug-likeness filter showed stable conformations during the molecular dynamics simulations. Among these, NuBBE_867 exhibited the best MM-PBSA binding free energy value compared to the crystallographic inhibitor. Therefore, this study suggests that NuBBE_867 could be a potential inhibitor against the main protease of SARS-CoV-2 and may be further examined to confirm our results.

Inhibitory effect of thymoquinone from Nigella sativa against SARS-CoV-2 main protease. An in-silico study / Efeito inibitório da timoquinona de Nigella sativa contra a principal protease do SARS-CoV-2. Um estudo in silico

Nigella sativa is known for the safety profile, containing a wealth of useful antiviral compounds. The main protease (Mpro, 3CLpro) of severe acute respiratory syndrome 2 (SARS-CoV-2) is being considered as one of the most attractive viral target, processing the polyproteins during viral pathogenesis and replication. In the current investigation we analyzed the potency of active component, thymoquinone (TQ) of Nigella sativa against SARS-CoV-2 Mpro. The structures of TQ and Mpro was retrieved from PubChem (CID10281) and Protein Data Bank (PDB ID 6MO3) respectively. The Mpro and TQ were docked and the complex was subjected to molecular dynamic (MD) simulations for a period 50ns. Protein folding effect was analyzed using radius of gyration (Rg) while stability and flexibility was measured, using root means square deviations (RMSD) and root means square fluctuation (RMSF) respectively. The simulation results shows that TQ is exhibiting good binding activity against SARS-CoV-2 Mpro, interacting many residues, present in the active site (His41, Cys145) and also the Glu166, facilitating the pocket shape. Further, experimental approaches are needed to validate the role of TQ against virus infection. The TQ is interfering with pocket maintaining residues as well as active site of virus Mpro which may be used as a potential inhibitor against SARS-CoV-2 for better management of COVID-19.

Nigella sativa é conhecida pelo perfil de segurança, contendo uma grande variedade de compostos antivirais úteis. A principal protease (Mpro, 3CLpro) da síndrome respiratória aguda grave 2 (SARS-CoV-2) está sendo considerada como um dos alvos virais mais atraentes, processando as poliproteínas durante a patogênese e replicação viral. Na presente investigação analisamos a potência do componente ativo, timoquinona (TQ) de Nigella sativa contra SARS-CoV-2 Mpro. As estruturas de TQ e Mpro foram recuperadas de PubChem (CID10281) e Protein Data Bank (PDB ID 6MO3), respectivamente. O Mpro e o TQ foram acoplados e o complexo foi submetido a simulações de dinâmica molecular (MD) por um período de 50ns. O efeito de dobramento de proteínas foi analisado usando o raio de giração (Rg) enquanto a estabilidade e a flexibilidade foram medidas usando a raiz quadrada média dos desvios (RMSD) e a raiz média quadrada da flutuação (RMSF), respectivamente. Os resultados da simulação mostram que o TQ está exibindo boa atividade de ligação contra o SARS-CoV-2 Mpro, interagindo em muitos resíduos presentes no sítio ativo (His41, Cys145) e também o Glu166, facilitando o formato da bolsa. Além disso, são necessárias abordagens experimentais para validar o papel do TQ contra a infecção pelo vírus. O TQ está interferindo nos resíduos de manutenção do bolso, bem como no sítio ativo do vírus Mpro, que pode ser usado como um potencial inibidor contra o SARS-CoV-2 para um melhor gerenciamento da Covid-19.

Inhibitory effects against SARSCoV-2 main protease (Mpro) of biflavonoids and benzophenones from the fruit of Platonia insignis.

The SARS-CoV-2 mutation and the limitation of the approved drug against COVID-19 are still a challenge in many country healthcare systems and need to be affronted despite the set of vaccines to prevent this viral infection. To contribute to the identification of new antiviral agents, the present study focused on natural products from an edible fruit with potential inhibitory effects against the SARS-CoV-2 main protease (Mpro). First, LC-ESIMS analysis of Platonia insignis fruits was performed and showed the presence of biflavonoids and benzophenones in the seed and pulp, respectively. Then, maceration and chromatographic purification led to the identification of two triglycerides (1 and 2) alongside chamaejasmine (3) and volkensiflavone (4) from the seed and isogarcinol (5) and cycloxanthochymol (6), from the pulp. Compounds 1-6 after evaluating their inhibitory against Mpro, displayed from no to significant activity. Compound 5 was the most potent with an IC50 value of 0.72 µM and was more active than the positive control, Ebselen (IC50 of 3.4 µM). It displayed weak and no cytotoxicity against THP-1 (CC50 of 116.2 µM) and Vero cell lines, respectively. Other active compounds showed no cytotoxicity against THP-1. and Vero cell lines. Molecular docking studies revealed interactions in the catalytic pocket between compound 5 and amino acid residues that composed the catalytic dyads (His 41 and Cyst 145).

Unveiling mutation effects on the structural dynamics of the main protease from SARS-CoV-2 with hybrid simulation methods.

The main protease of SARS-CoV-2 (called Mpro or 3CLpro) is essential for processing polyproteins encoded by viral RNA. Several Mpro mutations were found in SARS-CoV-2 variants, which are related to higher transmissibility, pathogenicity, and resistance to neutralization antibodies. Macromolecules adopt several favored conformations in solution depending on their structure and shape, determining their dynamics and function. In this study, we used a hybrid simulation method to generate intermediate structures along the six lowest frequency normal modes and sample the conformational space and characterize the structural dynamics and global motions of WT SARS-CoV-2 Mpro and 48 mutations, including mutations found in P.1, B.1.1.7, B.1.351, B.1.525 and B.1.429+B.1.427 variants. We tried to contribute to the elucidation of the effects of mutation in the structural dynamics of SARS-CoV-2 Mpro. A machine learning analysis was performed following the investigation regarding the influence of the K90R, P99L, P108S, and N151D mutations on the dimeric interface assembling of the SARS-CoV-2 Mpro. The parameters allowed the selection of potential structurally stable dimers, which demonstrated that some single surface aa substitutions not located at the dimeric interface (K90R, P99L, P108S, and N151D) are able to induce significant quaternary changes. Furthermore, our results demonstrated, by a Quantum Mechanics method, the influence of SARS-CoV-2 Mpro mutations on the catalytic mechanism, confirming that only one of the chains of the WT and mutant SARS-CoV-2 Mpros are prone to cleave substrates. Finally, it was also possible to identify the aa residue F140 as an important factor related to the increasing enzymatic reactivity of a significant number of SARS-CoV-2 Mpro conformations generated by the normal modes-based simulations.

Structural basis of nirmatrelvir and ensitrelvir activity against naturally occurring polymorphisms of the SARS-CoV-2 main protease.

SARS-CoV-2 is the causative agent of COVID-19. The main viral protease (Mpro) is an attractive target for antivirals. The clinically approved drug nirmatrelvir and the clinical candidate ensitrelvir have so far showed great potential for treatment of viral infection. However, the broad use of antivirals is often associated with resistance generation. Herein, we enzymatically characterized 14 naturally occurring Mpro polymorphisms that are close to the binding site of these antivirals. Nirmatrelvir retained its potency against most polymorphisms tested, while mutants G143S and Q189K were associated with diminished inhibition constants. For ensitrelvir, diminished inhibition constants were observed for polymorphisms M49I, G143S, and R188S, but not for Q189K, suggesting a distinct resistance profile between inhibitors. In addition, the crystal structures of selected polymorphisms revealed interactions that were critical for loss of potency. In conclusion, our data will assist the monitoring of potential resistant strains, support the design of combined therapy, as well as assist the development of the next generation of Mpro inhibitors.

The search for new efficient inhibitors of SARS-COV-2 through the De novo drug design developed by artificial intelligence.

The pandemic caused by Sars-CoV-2 is a viral infection that has generated one of the most significant health problems worldwide. Previous studies report the main protease (Mpro) as a potential target for this virus, as it is considered a crucial enzyme in mediating replication and viral transcription. This work presented the construction of new bioactive compounds for possible inhibition. The De novo molecular design of drugs method in the incremental construction of a ligant model within a receptor model was used, producing new structures with the help of artificial intelligence. The research algorithm and the scoring function responsible for predicting orientation and affinity in the molecular target at the time of coupling showed, as a result of the simulation, the compound with the highest bioaffinity value, Hit 998, with the energy of -17.62 kcal/mol, and synthetic viability close to 50%. While hit 1103 presented better synthetic viability (80%), its affinity energy of -10.28 kcal/mol. Both were compared with the reference linker N3, with a binding affinity of -7.5 kcal/mol. ADMET tests demonstrated that simulated compounds have a low risk of metabolic activation and do not exert effective distribution in the CNS, suggesting a pharmacokinetic mechanism based on local action, even with high topological polarity, which resulted in low oral bioavailability. In conclusion, MMGBSA, H-bonds, RMSD, SASA, and RMSF values were also obtained through molecular dynamics to verify the stability of the receptor-ligant complex within the active protein site to seek new therapeutic propositions in the fight against the pandemic.Communicated by Ramaswamy H. Sarma.

Absolute binding free energies of the antiviral peptide ATN-161 with protein targets of SARS-CoV-2.

The interactions of the antiviral pentapeptide ATN-161 with the closed and open conformations of the α5ß1 integrin, the SARS-CoV-2 major protease, and the omicron variant spike protein complexed with hACE2 were studied using molecular docking and molecular dynamics simulation. Molecular docking was performed to obtain ATN-161 binding poses with these studied protein targets. Subsequently, molecular dynamics simulations were performed to verify the ligand stability at the binding site of each protein target. Pulling simulations, umbrella sampling, and weighted histogram analysis method were used to obtain the potential of mean force of each system and calculate the Gibbs free energy of binding for the ATN-161 peptide in each binding site of these protein targets. The results showed that ATN-161 binds to α5ß1 integrin in its active and inactive form, binds weakly to the omicron variant spike protein complexed with hACE2, and strongly binds to the main protease target.Communicated by Ramaswamy H. Sarma.

A Review of Computational Approaches Targeting SARS-CoV-2 Main Protease to the Discovery of New Potential Antiviral Compounds.

The new pandemic caused by the coronavirus (SARS-CoV-2) has become the biggest challenge that the world is facing today. It has been creating a devastating global crisis, causing countless deaths and great panic. The search for an effective treatment remains a global challenge owing to controversies related to available vaccines. A great research effort (clinical, experimental, and computational) has emerged in response to this pandemic, and more than 125000 research reports have been published in relation to COVID-19. The majority of them focused on the discovery of novel drug candidates or repurposing of existing drugs through computational approaches that significantly speed up drug discovery. Among the different used targets, the SARS-CoV-2 main protease (Mpro), which plays an essential role in coronavirus replication, has become the preferred target for computational studies. In this review, we examine a representative set of computational studies that use the Mpro as a target for the discovery of small-molecule inhibitors of COVID-19. They will be divided into two main groups, structure-based and ligand-based methods, and each one will be subdivided according to the strategies used in the research. From our point of view, the use of combined strategies could enhance the possibilities of success in the future, permitting to development of more rigorous computational studies in future efforts to combat current and future pandemics.

A proteomics-MM/PBSA dual approach for the analysis of SARS-CoV-2 main protease substrate peptide specificity.

The main protease Mpro of SARS-CoV-2 is a well-studied major drug target. Additionally, it has been linked to this virus' pathogenicity, possibly through off-target effects. It is also an interesting diagnostic target. To obtain more data on possible substrates as well as to assess the enzyme's primary specificity a two-step approach was introduced. First, Terminal Amine Isobaric Labeling of Substrates (TAILS) was employed to identify novel Mpro cleavage sites in a mouse lung proteome library. In a second step, using a structural homology model, the MM/PBSA variant MM/GBSA (Molecular Mechanics Poisson-Boltzmann/Generalized Born Surface Area) free binding energy calculations were carried out to determine relevant interacting amino acids. As a result, 58 unique cleavage sites were detected, including six that displayed glutamine at the P1 position. Furthermore, modeling results indicated that Mpro has a far higher potential promiscuity towards substrates than expected. The combination of proteomics and MM/PBSA modeling analysis can thus be useful for elucidating the specificity of Mpro, and thus open novel perspectives for the development of future peptidomimetic drugs against COVID-19, as well as diagnostic tools.

SARS-COV-2 Mpro conformational changes induced by covalently bound ligands.

SARS-CoV-2's main protease (Mpro) interaction with ligands has been explored with a myriad of crystal structures, most of the monomers. Nonetheless, Mpro is known to be active as a dimer but the relevance of the dimerization in the ligand-induced conformational changes has not been fully elucidated. We systematically simulated different Mpro-ligand complexes aiming to study their conformational changes and interactions, through molecular dynamics (MD). We focused on covalently bound ligands (N1 and N3, ∼9 µs per system both monomers and dimers) and compared these trajectories against the apostructure. Our results suggest that the monomeric simulations led to an unrealistically flexible active site. In contrast, the Mpro dimer displayed a stable oxyanion-loop conformation along the trajectory. Also, ligand interactions with residues His41, Gly143, His163, Glu166 and Gln189 are postulated to impact the ligands' inhibitory activity significantly. In dimeric simulations, especially Gly143 and His163 have increased interaction frequencies. In conclusion, long-timescale MD is a more suitable tool for exploring in silico the activity of bioactive compounds that potentially inhibit the dimeric form of SARS-CoV-2 Mpro.Communicated by Ramaswamy H. Sarma.

Quantum biochemistry, molecular docking, and dynamics simulation revealed synthetic peptides induced conformational changes affecting the topology of the catalytic site of SARS-CoV-2 main protease.

The recent outbreak caused by SARS-CoV-2 continues to threat and take many lives all over the world. The lack of an efficient pharmacological treatments are serious problems to be faced by scientists and medical staffs worldwide. In this work, an in silico approach based on the combination of molecular docking, dynamics simulations, and quantum biochemistry revealed that the synthetic peptides RcAlb-PepI, PepGAT, and PepKAA, strongly interact with the main protease (Mpro) a pivotal protein for SARS-CoV-2 replication. Although not binding to the proteolytic site of SARS-CoV-2 Mpro, RcAlb-PepI, PepGAT, and PepKAA interact with other protein domain and allosterically altered the protease topology. Indeed, such peptide-SARS-CoV-2 Mpro complexes provoked dramatic alterations in the three-dimensional structure of Mpro leading to area and volume shrinkage of the proteolytic site, which could affect the protease activity and thus the virus replication. Based on these findings, it is suggested that RcAlb-PepI, PepGAT, and PepKAA could interfere with SARS-CoV-2 Mpro role in vivo. Also, unlike other antiviral drugs, these peptides have no toxicity to human cells. This pioneering in silico investigation opens up opportunity for further in vivo research on these peptides, towards discovering new drugs and entirely new perspectives to treat COVID-19.Communicated by Ramaswamy H. Sarma.

A proteomics-MM/PBSA dual approach for the analysis of SARS-CoV-2 main protease substrate peptide specificity

The main protease Mpro of SARS-CoV-2 is a well-studied major drug target. Additionally, it has been linked to this virus’ pathogenicity, possibly through off-target effects. It is also an interesting diagnostic target. To obtain more data on possible substrates as well as to assess the enzyme’s primary specificity a two-step approach was introduced. First, Terminal Amine Isobaric Labeling of Substrates (TAILS) was employed to identify novel Mpro cleavage sites in a mouse lung proteome library. In a second step, using a structural homology model, the MM/PBSA variant MM/GBSA (Molecular Mechanics Poisson-Boltzmann/Generalized Born Surface Area) free binding energy calculations were carried out to determine relevant interacting amino acids. As a result, 58 unique cleavage sites were detected, including six that displayed glutamine at the P1 position. Furthermore, modeling results indicated that Mpro has a far higher potential promiscuity towards substrates than expected. The combination of proteomics and MM/PBSA modeling analysis can thus be useful for elucidating the specificity of Mpro, and thus open novel perspectives for the development of future peptidomimetic drugs against COVID-19, as well as diagnostic tools.

Working goal of Brazilein sappan wood as a candidate for SARS-coV-2 antivirus drug against spike (S) glycoprotein, papain-like proteinase, and main protease: In silico study.

Brazilein sappan wood, played by Spike (S) glycoprotein, Papain-Like proteinase (PLpro), and Main protease (Mpro), is expected to be a candidate for the antiviral drug SARS-CoV-2, which can inhibit viral attachment to the human body, replication, and transcription processes. The aim of this study was to predict in silico, using the comparative drug hydroxychloroquine, the working goal of brazilein sappan wood as a candidate for the antiviral drug SARS-CoV-2 against protein S, PLpro, and Mpro. The approach used is the in silico docking test using the computer program Molegro Virtual Docker. Receptor used by protein S, Protein Data Bank (PDB) code: 6M0J, NAG_601[E] ligand; PLpro, PDB code: 7JIT, Y95_501[A] ligand; and Mpro, PDB code: 1WOF, I12_1145[A] ligand. Data analysis was carried out by comparing the docking bond energies between the ligands at the target receptor. Silico test results for protein S: ligand bond energy NAG_601 [E] = -59.4555, brazilein = -71.5537, hydroxychloroquine = -79.3704; PLpro protein: Ligand bond energy Y95_501 [A] = -129.561, brazilein = -94.9761, hydroxychloroquine = -100.984; Mpro protein: Ligand bond energy I12 1145 [A] = -141.135, brazilein = -96.6169, hydroxychloroquine = -104.88. The above test results indicate that brazilein sappan wood has potential as a SARS-CoV-2 drug candidate, has a stable bond, and that the biological activity of the compound is stronger against S protein than the proteins of PLpro and Mpro.

Identification of known drugs as potential SARS-CoV-2 Mpro inhibitors using ligand- and structure-based virtual screening.

Background: The new coronavirus pandemic has had a significant impact worldwide, and therapeutic treatment for this viral infection is being strongly pursued. Efforts have been undertaken by medicinal chemists to discover molecules or known drugs that may be effective in COVID-19 treatment - in particular, targeting the main protease (Mpro) of the virus. Materials & methods: We have employed an innovative strategy - application of ligand- and structure-based virtual screening - using a special compilation of an approved and diverse set of SARS-CoV-2 crystallographic complexes that was recently published. Results and conclusion: We identified seven drugs with different original indications that might act as potential Mpro inhibitors and may be preferable to other drugs that have been repurposed. These drugs will be experimentally tested to confirm their potential Mpro inhibition and thus their effectiveness against COVID-19.

In Silico Characterization of Masitinib Interaction with SARS-CoV-2 Main Protease.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection continues to be a global health problem. Despite the current implementation of COVID-19 vaccination schedules, identifying effective antiviral drug treatments for this disease continues to be a priority. A recent study showed that masitinib (MST), a tyrosine kinase inhibitor, blocks the proteolytic activity of SARS-CoV-2 main protease (Mpro ). Although MST is a potential candidate for COVID-19 treatment, a comprehensive analysis of its interaction with Mpro has not been done. In this work, we performed molecular dynamics simulations of the MST-Mpro complex crystal structure. The effect of the protonation states of Mpro H163 residue and MST titratable groups were studied. Furthermore, we identified the MST substituents and Mpro mutations that affect the stability of the complex. Our results provide valuable insights into the design of new MST analogs as potential treatments for COVID-19.

Protein-Ligand Docking Simulations with AutoDock4 Focused on the Main Protease of SARS-CoV-2.

BACKGROUND: The main protease of SARS-CoV-2 (Mpro) is one of the targets identified in SARS-CoV-2, the causative agent of COVID-19. The application of X-ray diffraction crystallography made available the three-dimensional structure of this protein target in complex with ligands, which paved the way for docking studies. OBJECTIVE: Our goal here is to review recent efforts in the application of docking simulations to identify inhibitors of the Mpro using the program AutoDock4. METHODS: We searched PubMed to identify studies that applied AutoDock4 for docking against this protein target. We used the structures available for Mpro to analyze intermolecular interactions and reviewed the methods used to search for inhibitors. RESULTS: The application of docking against the structures available for the Mpro found ligands with an estimated inhibition in the nanomolar range. Such computational approaches focused on the crystal structures revealed potential inhibitors of Mpro that might exhibit pharmacological activity against SARS-CoV-2. Nevertheless, most of these studies lack the proper validation of the docking protocol. Also, they all ignored the potential use of machine learning to predict affinity. CONCLUSION: The combination of structural data with computational approaches opened the possibility to accelerate the search for drugs to treat COVID-19. Several studies used AutoDock4 to search for inhibitors of Mpro. Most of them did not employ a validated docking protocol, which lends support to critics of their computational methodology. Furthermore, one of these studies reported the binding of chloroquine and hydroxychloroquine to Mpro. This study ignores the scientific evidence against the use of these antimalarial drugs to treat COVID-19.

Field-Template, QSAR, Ensemble Molecular Docking, and 3D-RISM Solvation Studies Expose Potential of FDA-Approved Marine Drugs as SARS-CoVID-2 Main Protease Inhibitors.

Currently, SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2) has infected people among all countries and is a pandemic as declared by the World Health Organization (WHO). SARS-CoVID-2 main protease is one of the therapeutic drug targets that has been shown to reduce virus replication, and its high-resolution 3D structures in complex with inhibitors have been solved. Previously, we had demonstrated the potential of natural compounds such as serine protease inhibitors eventually leading us to hypothesize that FDA-approved marine drugs have the potential to inhibit the biological activity of SARS-CoV-2 main protease. Initially, field-template and structure-activity atlas models were constructed to understand and explain the molecular features responsible for SARS-CoVID-2 main protease inhibitors, which revealed that Eribulin Mesylate, Plitidepsin, and Trabectedin possess similar characteristics related to SARS-CoVID-2 main protease inhibitors. Later, protein-ligand interactions are studied using ensemble molecular-docking simulations that revealed that marine drugs bind at the active site of the main protease. The three-dimensional reference interaction site model (3D-RISM) studies show that marine drugs displace water molecules at the active site, and interactions observed are favorable. These computational studies eventually paved an interest in further in vitro studies. Finally, these findings are new and indeed provide insights into the role of FDA-approved marine drugs, which are already in clinical use for cancer treatment as a potential alternative to prevent and treat infected people with SARS-CoV-2.

Application of green synthesised copper iodide particles on cotton fabric-protective face mask material against COVID-19 pandemic.

Microorganisms cause variety of diseases that constitutes a severe threat to mankind. Due to the upsurge of many infectious diseases, there is a high requirement and demand for the development of safety products finished with antimicrobial properties. The study involves the antimicrobial activity of natural cotton coated with copper iodide capped with Hibiscus rosa-sinensis L. flower extract (CuI-FE) which is rich in anthocyanin, cyanidin-3-sophoroside by ultrasonication method. The coated and uncoated cotton fabric was characterised through XRD, SEM, AFM, tensile strength and UV-Visible spectroscopic techniques. XRD confirmed the formation of CuI particles, SEM showed that CuI-FE was prismatic in shape. The average size of CuI-FE particles was found to be 552.45 nm. Anti-bacterial studies showed copper iodide particles to be a potent antimicrobial agent. AFM images confirmed the rupture of bacterial cell walls in the presence of prismatic CuI-FE. In-vitro cytotoxicity investigation of CuI-FE was performed against cancer and spleen cell lines to evaluate the cell viability. Cytotoxicity analysis revealed the IC50 value of 233.93 µg/mL in the presence of CuI-FE. Molecular docking study was also carried out to understand the interaction of CuI-FE with COVID-19 main protease. This paper has given an insight on the usage of CuI-FE coated on the cotton fabric that has proved to have strong inhibition against the nano ranged bacterial, cancerous cell line and a strong interaction with the COVID-19 protease. Such eco-friendly material will provide a safe environment even after the disposable of medical waste from the infectious diseases like influenza and current pandemic like COVID-19.

Mutations in Main Protease of SARS CoV-2 Decreased Boceprevir Affinity

Abstract The coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a global health emergency. The main protease (Mpro) is crucial for the life cycle of coronaviruses. Boceprevir is a potential inhibitor and drug candidate for the Mpro of SARS-CoV-2. In this study, changes in the protein structure of the Mpro due to mutations in SARS-CoV-2 and the effects of these changes on boceprevir affinity, an important potential therapeutic agent, were investigated. The mutations were analyzed with RDP4 and MegaX. A three-dimensional model of mutant Mpro was generated by ProMod3. Qualitative Model Energy Analysis, ProSA, and MolProbity tools were used for structural validation and modeling of the wild-type and mutant Mpro proteins. Topological differences of the wild-type and mutant Mpro were calculated with the i-Tasser TM-Score. Molecular docking was performed using AutoDock 4.2. Functional dynamic structure models were created with DynOmics. Seven mutations (L89F, K90R, P108S, A191V, T224A, A234V and S254F) were detected in the Mpro of SARS-CoV-2. The mutations caused a decrease in the affinity of boceprevir, a potential protease inhibitor. The boceprevir was docked to the active site of Mpro, and the binding energies were −10.34 and −9.41 kcal.mol-1 for the wild-type and the mutant, respectively. The Debye-Waller factors calculated by elastic network model analysis were 0.58 and 0.64 Å2 for the wild-type Mpro and mutant Mpro, respectively. Mutations in structures that are important drug targets for SARS-CoV-2 may render existing therapeutics ineffective in its treatment.