Coronavirus Main Protease Research Articles

Synthesis of novel coumarin analogues: Investigation of molecular docking interaction of SARS-CoV-2 proteins with natural and synthetic coumarin analogues and their pharmacokinetics studies.

The severe acute respiratory syndrome coronavirus, identified as SARS-CoV-2, initially established in Wuhan, China at the end of 2019, affects respiratory infections known as COVID-19. In an extraordinary manner, COVID-19 is affecting human life and has transformed a global public health issue into a crisis. Natural products are already recognized owing to the massive advantageous window and efficient antioxidant, antiviral immunomodulatory, and anti-inflammatory belongings. Additionally, the object of the present study was to demonstrate the inhibitory potential of the natural products coumarins and its analogues alongside SARS coronavirus. The present work, focuses on the synthesis of new coumarin analogues and characterized by FT-IR, 1H and 13C NMR, elemental analyses, and mass spectra. The recently synthesised compounds were projected conceptual association for COVID-19 protease and also to explore in anticipation if this protein will help target protease inhibitor drugs such as Calanolide A, Cardatolide A, Collinin, Inophyllum A, Mesuol, Isomesuol, Pteryxin, Rutamarin, Seselin and Suksdorin. The natural coumarin analogues docking scores were compared to standard Hydroxychloroquine. While the 3D module of SARS coronavirus main protease was predicted with the SWISS MODEL web server, as well as biochemical interaction tests were performed with the AutoDock Vina tool between the target protein with ligands. This research further showed that all the protease inhibitors accessed the target protein with negative dock energy. Molecular docking studies found that the natural coumarin analogue Inophyllum A showed an exceptional potential for inhibition with a binding energy of −8.4 kcal/mol. The synthetic coumarin analogues 1m and 1p both demonstrated a similar binding energy, inhibition potential of −7.9 kcal / mol as opposed to hydroxychloroquine and co-crystallized ligand alpha-ketoamide with binding energy values of −5.8 and −6.6 kcal / mol. All compounds evaluated were known as drug-like in nature, passing Lipinski's “Law of 5” with 0 violations except for alpha-ketoamide, passing Lipinski's “Rule of 5” with 1 violation (MW > 500). The inhibitor binding in silico research thus offers a structural understanding of COVID-19 and molecular interactions across the known protease inhibitors centred on the findings of the multiple sequence alliance.

Probing the Dynamic Structure-Function and Structure-Free Energy Relationships of the Coronavirus Main Protease with Biodynamics Theory.

The SARS-CoV-2 main protease (Mpro) is of major interest as an antiviral drug target. Structure-based virtual screening efforts, fueled by a growing list of apo and inhibitor-bound SARS-CoV/CoV-2 Mpro crystal structures, are underway in many laboratories. However, little is known about the dynamic enzyme mechanism, which is needed to inform both assay development and structure-based inhibitor design. Here, we apply biodynamics theory to characterize the structural dynamics of substrate-induced Mpro activation under nonequilibrium conditions. The catalytic cycle is governed by concerted dynamic structural rearrangements of domain 3 and the m-shaped loop (residues 132–147) on which Cys145 (comprising the thiolate nucleophile and half of the oxyanion hole) and Gly143 (comprising the second half of the oxyanion hole) reside. In particular, we observed the following: (1) Domain 3 undergoes dynamic rigid-body rotation about the domain 2–3 linker, alternately visiting two primary conformational states (denoted as M1pro ↔ M2pro); (2) The Gly143-containing crest of the m-shaped loop undergoes up and down translations caused by conformational changes within the rising stem of the loop (Lys137–Asn142) in response to domain 3 rotation and dimerization (denoted as M1/downpro ↔ 2·M2/uppro) (noting that the Cys145-containing crest is fixed in the up position). We propose that substrates associate to the M1/downpro state, which promotes the M2/downpro state, dimerization (denoted as 2·M2/uppro–substrate), and catalysis. Here, we explore the state transitions of Mpro under nonequilibrium conditions, the mechanisms by which they are powered, and the implications thereof for efficacious inhibition under in vivo conditions.

Potential therapeutic target identification in the novel 2019 coronavirus: insight from homology modeling and blind docking study

BackgroundThe 2019-nCoV which is regarded as a novel coronavirus is a positive-sense single-stranded RNA virus. It is infectious to humans and is the cause of the ongoing coronavirus outbreak which has elicited an emergency in public health and a call for immediate international concern has been linked to it. The coronavirus main proteinase which is also known as the 3C-like protease (3CLpro) is a very important protein in all coronaviruses for the role it plays in the replication of the virus and the proteolytic processing of the viral polyproteins. The resultant cytotoxic effect which is a product of consistent viral replication and proteolytic processing of polyproteins can be greatly reduced through the inhibition of the viral main proteinase activities. This makes the 3C-like protease of the coronavirus a potential and promising target for therapeutic agents against the viral infection.ResultsThis study describes the detailed computational process by which the 2019-nCoV main proteinase coding sequence was mapped out from the viral full genome, translated and the resultant amino acid sequence used in modeling the protein 3D structure. Comparative physiochemical studies were carried out on the resultant target protein and its template while selected HIV protease inhibitors were docked against the protein binding sites which contained no co-crystallized ligand.ConclusionIn line with results from this study which has shown great consistency with other scientific findings on coronaviruses, we recommend the administration of the selected HIV protease inhibitors as first-line therapeutic agents for the treatment of the current coronavirus epidemic.

Research on Covid-19 from Biophysical Perspective

In this report, we discuss the current aspect of biophysics which is an essential field to investigate the structural and related properties of SARS-CoV-2 components, possible drugs likeliness and their interactions, and mathematical as well as clinical data modeling. We have emphasized that a mathematical model generates the sigmoid logistic equation that predicts the total corona virus cases and deaths in a model country with population averaged from the most vulnerable countries, such as India or USA, where the COVID-19 cases are still spiking up and from the countries which are on the process of recovering from the current pandemic. Further, the current status of COVID-19 research has been explained to understand its impacts taking Nepal as the reference country having low-income. In particular, focus is on biophysical study on structural analysis of novel coronavirus main protease which is found to influence the radial distributions of H-bonding atom pairs when interacting with the inhibitors N3. Explorations of the variations of physical parameters are found to be important in drug selective mechanism against COVID-19 infections.

Both Boceprevir and GC376 efficaciously inhibit SARS-CoV-2 by targeting its main protease

COVID-19 was declared a pandemic on March 11 by WHO, due to its great threat to global public health. The coronavirus main protease (Mpro, also called 3CLpro) is essential for processing and maturation of the viral polyprotein, therefore recognized as an attractive drug target. Here we show that a clinically approved anti-HCV drug, Boceprevir, and a pre-clinical inhibitor against feline infectious peritonitis (corona) virus (FIPV), GC376, both efficaciously inhibit SARS-CoV-2 in Vero cells by targeting Mpro. Moreover, combined application of GC376 with Remdesivir, a nucleotide analogue that inhibits viral RNA dependent RNA polymerase (RdRp), results in sterilizing additive effect. Further structural analysis reveals binding of both inhibitors to the catalytically active side of SARS-CoV-2 protease Mpro as main mechanism of inhibition. Our findings may provide critical information for the optimization and design of more potent inhibitors against the emerging SARS-CoV-2 virus.

Amoxicillin and Clavulanate as Potential Multiple Effect Inhibitors of 2019 Novel Coronavirus Main Protease and RNA-Dependent RNA Polymerase with Strong Receptor-Binding Domain (RBD), Molecular Docking and SAR Study

SARS-CoV-2 is a novel coronavirus was isolated and identified first time in 2019 in Wuhan, China. Nowadays, it is a worldwide danger and the WHO named it as a pandemic. With a number of 5,593,631 as confirmed cases, and 353,334 as deaths. On 17 February, we have started our researches for finding potential inhibitors for COVID-19 main protease, especially after publishing the first crystalline structure of this protein in the PDB with PDB ID: 6lu7. We have found three potent molecules Hispidin, Folic acid and Lepidine E with Ki values 5.21, 3.71 and 1.89 μM respectively. Continuing the same context and in order to determine more inhibitors as potential strategy for COVID-19 treatment by molecular docking. We detected Amoxicillin and clavulanate as very strong inhibitors with a rate of 100% to the nCov-19 main protease and RNA-dependent RNA polymerase by several hydrogen bonds and hydrophobic interactions. In addition, we have docked both inhibitors to Spike protein domain of the virus responsible for its binding to the ACE2 receptors in the lungs and other vital organs. The results show that the ligands bound tightly with this latter confirming multiple effect and target of the drugs. Funding Statement: DGRSDT of Algeria Declaration of Interests: None to declare Ethics Approval Statement: Not needed

Natural derivatives with dual binding potential against SARS-CoV-2 main protease and human ACE2 possess low oral bioavailability: a brief computational analysis

The world is witnessing severe health meltdown due to COVID-19. Generic antiviral drug remdesivir has been found to reduce time to clinical recovery but with insignificant clinical benefits and the antimalarial drug, hydroxychloroquine has been red flagged by USFDA for use as a prophylactic measure due to its cardiotoxicity. There is an acute requirement for a drug candidate that has significant clinical benefit with minimal to no side effects. With restricted access to wet laboratory techniques, an alternative approach is to engage in computational screening of lead molecules that could inhibit SARS-CoV-2 at different stages of its infectious cycle. Several in silico studies on natural derivatives, especially that present in daily refreshments (tea and fruit juices), staple food (black rice, red onions, soy beans etc) and traditional medicines (extracts of herbs, leaves and flowers) have been identified as potential drug candidates that bind efficiently with the key viral proteins. However, oral bioavailability of these nutriments is considerably low due to either poor permeability or loss of structure and function due to digestion in the gastrointestinal tract. Here we discuss few natural secondary metabolites (Delphinidin 3,5-diglucoside, Scutellarein 7-glucoside, Avicularin and 3,5-Di-O-galloylshikimic acid) that showed encouraging binding affinity against coronavirus main protease (Mpro) and human ACE2 receptor with MM-GBSA energies up to −74.0 Kcal/mol and −79.5 Kcal/mol, respectively. However, their Abbott bioavailability score (ABS) of 0.11 or 0.17 predicts poor oral bioavailability. This study could trigger interest to engineer potential natural products in managing present or future pandemics. Communicated by Ramaswamy H. Sarma

Distorted Key Theory and its Implication for Drug Development

During the last three decades or so, many efforts have been made to study the protein cleavage sites by some disease-causing enzyme, such as HIV (Human Immunodeficiency Virus) protease and SARS (Severe Acute Respiratory Syndrome) coronavirus main proteinase. It has become increasingly clear <i>via</i> this mini-review that the motivation driving the aforementioned studies is quite wise, and that the results acquired through these studies are very rewarding, particularly for developing peptide drugs.

Structure-based screening of novel lichen compounds against SARS Coronavirus main protease (Mpro) as potentials inhibitors of COVID-19.

The outbreak of SARS-CoV-2 and deaths caused by it all over the world have imposed great concern on the scientific community to develop potential drugs to combat Coronavirus disease-19 (COVID-19). In this regard, lichen metabolites may offer a vast reservoir for the discovery of antiviral drug candidates. Therefore, to find novel compounds against COVID-19, we created a library of 412 lichen compounds and subjected to virtual screening against the SARS-CoV-2 Main protease (Mpro). All the ligands were virtually screened, and 27 compounds were found to have high affinity with Mpro. These compounds were assessed for drug-likeness analysis where two compounds were found to fit well for redocking studies. Molecular docking, drug-likeness, X-Score, and toxicity analysis resulting in two lichen compounds, Calycin and Rhizocarpic acid with Mpro-inhibiting activity. These compounds were finally subjected to molecular dynamics simulation to compare the dynamics behavior and stability of the Mpro after ligand binding. The binding energy was calculated by MM-PBSA method to determine the intermolecular protein–ligand interactions. Our results showed that two compounds; Calycin and Rhizocarpic acid had the binding free energy of − 42.42 kJ mol/1 and − 57.85 kJ mol/1 respectively as compared to reference X77 (− 91.78 kJ mol/1). We concluded that Calycin and Rhizocarpic acid show considerable structural and pharmacological properties and they can be used as hit compounds to develop potential antiviral agents against SARS-CoV-2. These lichen compounds may be a suitable candidate for further experimental analysis.Graphic abstract Electronic supplementary materialThe online version of this article (10.1007/s11030-020-10118-x) contains supplementary material, which is available to authorized users.

Evaluation of green tea polyphenols as novel corona virus (SARS CoV-2) main protease (Mpro) inhibitors – an in silico docking and molecular dynamics simulation study

Coronavirus disease 2019 (COVID-19) is a viral respiratory disease which caused global health emergency and announced as pandemic disease by World Health Organization. Lack of specific drug molecules or treatment strategy against this disease makes it more devastating. Thus, there is an urgent need of effective drug molecules to fight against COVID-19. The main protease (Mpro) of SARS CoV-2, a key component of this viral replication, is considered as a prime target for anti-COVID-19 drug development. In order to find potent Mpro inhibitors, we have selected eight polyphenols from green tea, as these are already known to exert antiviral activity against many RNA viruses. We have elucidated the binding affinities and binding modes between these polyphenols including a well-known Mpro inhibitor N3 (having binding affinity −7.0 kcal/mol) and Mpro using molecular docking studies. All eight polyphenols exhibit good binding affinity toward Mpro (−7.1 to −9.0 kcal/mol). However, only three polyphenols (epigallocatechin gallate, epicatechingallate and gallocatechin-3-gallate) interact strongly with one or both catalytic residues (His41 and Cys145) of Mpro. Molecular dynamics simulations (100 ns) on these three Mpro–polyphenol systems further reveal that these complexes are highly stable, experience less conformational fluctuations and share similar degree of compactness. Estimation of total number of intermolecular H-bond and MM-GBSA analysis affirm the stability of these three Mpro–polyphenol complexes. Pharmacokinetic analysis additionally suggested that these polyphenols possess favorable drug-likeness characteristics. Altogether, our study shows that these three polyphenols can be used as potential inhibitors against SARS CoV-2 Mpro and are promising drug candidates for COVID-19 treatment.

CORDITE: The Curated CORona Drug InTERactions Database for SARS-CoV-2.

SummarySince the outbreak in 2019, researchers are trying to find effective drugs against the SARS-CoV-2 virus based on de novo drug design and drug repurposing. The former approach is very time consuming and needs extensive testing in humans, whereas drug repurposing is more promising, as the drugs have already been tested for side effects, etc. At present, there is no treatment for COVID-19 that is clinically effective, but there is a huge amount of data from studies that analyze potential drugs.We developed CORDITE to efficiently combine state-of-the-art knowledge on potential drugs and make it accessible to scientists and clinicians. The web interface also provides access to an easy-to-use API that allows a wide use for other software and applications, e.g., for meta-analysis, design of new clinical studies, or simple literature search. CORDITE is currently empowering many scientists across all continents and accelerates research in the knowledge domains of virology and drug design.

The virtual screening application for searching potential antiviral agents to treat COVID-19 disease

Aim. To provide a brief literature review regarding the structure of the human coronavirus SARS-CoV-2, the mechanism of its replication and the role of viral proteases in this process; to analyze the ability of the known antiviral agents and compounds synthesized de novo in order to bind and inhibit the coronavirus main protease using computer simulation tools.Results and discussion. COVID-19 coronavirus has become a worldwide challenge in recent months. Taking into account the rapid spread and severity of COVID-19 among a significant part of the population there is an urgent need to develop effective medicines and appropriate treatment protocols, which, unfortunately, are not yet available. Currently, the search for molecules with an acceptable toxicity profile that are able to inhibit and/or stop coronavirus SARS-CoV-2 replication in the human body is very relevant. In this study, the virtual screening and molecular docking of both antiviral agents known and new compounds synthesized have been performed based on the structure of the main protease Mpro of SARS-CoV-2. The regularities identified during our study can be useful for searching and developing new antiviral drugs to control COVID-19 and other coronavirus infections. The analysis of the results of calculations of physicochemical characteristics of antiviral agents, as well as the determination of their binding sites with the main viral protease Mpro gives an optimistic assessment of the possibility to develop new drugs based on the structures of the known antiviral drugs or their modified analogs.Experimental part. Based on recent studies of the crystal structure of the virus main protease Mpro in the complex with various inhibitors (Protein Data Bank http://www.rcsb.org/pdb, the structure code – 6LU7) the virtual screening and molecular docking of 100 known antiviral agents and 50 novel compounds synthesized were performed. The screening data for the in vitro antimalarial activity of the compounds synthesized were presented. The following binding and physicochemical parameters of the ligand–protein interaction for all virus main protease potential inhibitors were calculated: binding affinity score (BAS), binding energy, lipophilicity (clogP) and topological polar surface area (TPSA). The protein and ligand structures were studied using Jmol, PyMol, and Avogadro graphics software packages. The virtual screening and molecular docking, as well as the analysis of the results were performed using a LigandScout 4.4 software package. Data on the antimalarial activity of 50 compounds synthesized were obtained from the Laboratory of Microbiology, Parasitology and Hygiene of theUniversity ofAntwerp (Belgium).Conclusions. According to the results of the virtual screening and molecular docking with protein 6LU7 it has been found that a number of the known antiviral drugs have a certain potential for their use as inhibitors of SARS-CoV-2 coronavirus main protease. Remdesivir and ritonavir substances have shown higher activity than the reference compound of the 6LU7 complex. The molecular docking of a series of compounds recently synthesized with the proven in vitro antimalarial activity has revealed that L1 – L6 compounds are promising candidates for further modification and development of new antiviral drugs to control coronavirus infection.Received: 02.04.2020Revised: 23.05.2020Accepted: 29.05.2020

In silico screening of FDA approved drugs reveals ergotamine and dihydroergotamine as potential coronavirus main protease enzyme inhibitors.

Coronaviruses with the largest viral genomes are positive-sense RNA viruses associated with a history of global epidemics such as the severe respiratory syndrome (SARS), the Middle East respiratory syndrome (MERS) and recently the coronavirus disease 2019 (COVID-19). There has been no vaccines or drugs available for the treatment of human coronavirus infections to date. In the present study, we have explored the possibilities of FDA approved drugs as potential inhibitors of the coronavirus main protease, a therapeutically important drug target playing a salient role in the maturation and processing of the viral polyproteins and are vital for viral replication and transcription. We have used molecular docking approach and have successfully identified the best lead molecules for each enzyme target. Interestingly, the anti-migraine drugs such as ergotamine and its derivative, dihydroergotamine were found to bind to all the three target enzymes within the Cys-His catalytic dyad cleft with lower binding energies as compared to the control inhibitors (α-ketoamide 13b, SG85 and GC813) and the molecules are held within the pocket through a good number of hydrogen bonds and hydrophobic interactions. Hence both these lead molecules can be further taken for wet-lab experimentation studies before repurposing them as anti-coronaviral drug candidates.

Fragment tailoring strategy to design novel chemical entities as potential binders of novel corona virus main protease

The recent pandemic of severe acute respiratory syndrome–coronavirus2 (SARS-CoV-2) infection (COVID-19) has put the world on serious alert. The main protease of SARS-CoV-2 (SARS-CoV-2-MPro) cleaves the long polyprotein chains to release functional proteins required for replication of the virus and thus is a potential drug target to design new chemical entities in order to inhibit the viral replication in human cells. The current study employs state of art computational methods to design novel molecules by linking molecular fragments which specifically bind to different constituent sub-pockets of the SARS-CoV-2-MPro binding site. A huge library of 191678 fragments was screened against the binding cavity of SARS-CoV-2-MPro and high affinity fragments binding to adjacent sub-pockets were tailored to generate new molecules. These newly formed molecules were further subjected to molecular docking, ADMET filters and MM-GBSA binding energy calculations to select 17 best molecules (named as MP-In1 to MP-In17), which showed comparable binding affinities and interactions with the key binding site residues as the reference ligand. The complexes of these 17 molecules and the reference molecule with SARS-CoV-2-MPro, were subjected to molecular dynamics simulations, which assessed the stabilities of their binding with SARS-CoV-2-MPro. Fifteen molecules were found to form stable complexes with SARS-CoV-2-MPro. These novel chemical entities designed specifically according to the pharmacophoric requirements of SARS-CoV-2-MPro binding pockets showed good synthetic feasibility and returned no exact match when searched against chemical databases. Considering their interactions, binding efficiencies and novel chemotypes, they can be further evaluated as potential starting points for SARS-CoV-2 drug discovery.

Molecular docking analysis of N-substituted oseltamivir derivatives with the SARS-Cov-2 main protease

The identification of chemotherapeutic drugs against Novel Coronavirus (2019-nCoV) is a significant requirement due to the rapid rise in deaths due to Corona Viral Infection all around the world. Therefore, it is of interest to document the molecular docking analysis data of 32 N-substituted Oseltamivir derivatives inhibitors of influenza virus H5N1 with the Novel Coronavirus main protease (2019-nCoV). We describe the optimal binding features of Oseltamivir derivatives with the SARS-Cov-2 main protease (Code PDB: 6LU7) for further consideration.

Views on Structure-based design of antiviral drug candidates targeting the SARS-CoV-2 main protease by Dai et al. (2020).

The project for the report Dai et al. (2020) [1] seems to be well funded and the authors had access to many modern facilities and techniques. They were able to successfully design, synthesize and evaluate two lead inhibitors of SARS-CoV-2 main protease. Interestingly, they were able to crystallize protease-inhibitor complex to visualize real chemical interaction involved. According to x-ray diffraction images, they found that the aldehyde group of synthesized inhibitors is involved in covalent bond with Mpro active site. We can appreciate this finding by noting that computational modeling approaches like docking studies have difficulties in predicting covalent bonds. The design of these two novel inhibitors may be considered a continuation for several previous attempts of structure-based design of coronavirus main protease inhibitors, for example the well-known peptide inhibitor N3. I am only concerned about the interaction between lead inhibitors and water molecules in crystallization images. These water molecules may be active site reserved water or merely the result of crystallization process. It would be interesting to prepare several derivatives of these two lead inhibitors and then establish a structure-activity relationship study. This seems to be crucial for elucidating the structure of core scaffold.

In silico fight against novel coronavirus by finding chromone derivatives as inhibitor of coronavirus main proteases enzyme.

Novel coronavirus, 2019-nCoV is a danger to the world and is spreading rapidly. Very little structural information about 2019-nCoV make this situation more difficult for drug designing. Benzylidenechromanones, naturally occurring oxygen heterocyclic compounds, having capability to inhibit various protein and receptors, have been designed here to block mutant variety of coronavirus main protease enzyme (SARC-CoV-2 Mpro) isolated from 2019-nCoV with the assistance of molecular docking, bioinformatics and molecular electrostatic potential. (Z)-3-(4′-chlorobenzylidene)-thiochroman-4-one showed highest binding affinity to the protein. Binding of a compound to this protein actually inhibits the replication and transcription of the virus and, ultimately, stop the virus multiplication. Incorporation of any functional groups to the basic benzylidenechromanones enhances their binding ability. Chloro and bromo substitutions amplify the binding affinity. ADME studies of all these compounds indicate they are lipophilic, high gastro intestine absorbable and blood-brain barrier permeable. The outcome reveals that the investigated benzylidenechromanones can be examined in the case of 2019-nCoV as potent inhibitory drug of SARC-CoV-2 Mpro, for their strong inhibition ability, high reactivity and effective pharmacological properties.Electronic supplementary materialThe online version of this article (10.1007/s11224-020-01537-5) contains supplementary material, which is available to authorized users.

Moroccan Medicinal plants as inhibitors against SARS-CoV-2 main protease: Computational investigations

The new Corona-virus, recently called the severe acute respiratory syndrome Coronavirus (SARS-CoV-2) appears for the first time in China and more precisely in Wuhan (December 2019). This disease can be fatal. Seniors, and people with other medical conditions (diabetes, heart disease…), may be more vulnerable and become seriously ill. This is why research into drugs to treat this infection remains essential in several research laboratories. Natural herbal remedies have long been the main, if not the only, remedy in the oral tradition for treating illnesses. Modern medicine has known its success thanks to traditional medicine, the effectiveness of which derives from medicinal plants. The objective of this study is to determine if the components of natural origin have an anti-viral effect and which can prevent humans from infection by this coronavirus using the most reliable method is molecular docking, which used to find the interaction between studied molecules and the protein, in our case we based on the inhibitor of Coronavirus (nCoV-2019) main protease. The results of molecular docking showed that among 67 molecules of natural origin, three molecules (Crocin, Digitoxigenin, and β-Eudesmol) are proposed as inhibitors against the coronavirus based on the energy types of interaction between these molecules and studied protein. Communicated by Ramaswamy H. Sarma Highlights Determine natural compounds that can have an anti-viral effect and which can prevent humans from infection by this coronavirus; Molecular docking to find interaction between the molecules studied and the receptor of COVID-19; The synthesis of these molecules and the evaluation of their in vitro activity against SARS-Cov-2 could be interesting.

Identification of new anti-nCoV drug chemical compounds from Indian spices exploiting SARS-CoV-2 main protease as target

The 2019-novel coronavirus (nCoV) has caused a global health crisis by causing coronavirus disease-19 (COVID-19) pandemic in the human population. The unavailability of specific vaccines and anti-viral drug for nCoV, science demands sincere efforts in the field of drug design and discovery for COVID-19. The novel coronavirus main protease (SARS-CoV-2 Mpro) play a crucial role during the disease propagation, and hence SARS-CoV-2 Mpro represents as a drug target for the drug discovery. Herein, we have applied bioinformatics approach for screening of chemical compounds from Indian spices as potent inhibitors of SARS-CoV-2 main protease (PDBID: 6Y84). The structure files of Indian spices chemical compounds were taken from PubChem database or Zinc database and screened by molecular docking, by using AutoDock-4.2, MGLTools-1.5.6, Raccoon virtual screening tools. Top 04 hits based on their highest binding affinity were analyzed. Carnosol exhibited highest binding affinity -8.2 Kcal/mol and strong and stable interactions with the amino acid residues present on the active site of SARS-CoV-2 Mpro. Arjunglucoside-I (-7.88 Kcal/mol) and Rosmanol (-7.99 Kcal/mol) also showed a strong and stable binding affinity with favourable ADME properties. These compounds on MD simulations for 50 ns shows strong hydrogen-bonding interactions with the protein active site and remains stable inside the active site. Our virtual screening results suggest that these small chemical molecules can be used as potential inhibitors against SARS-CoV-2 Mpro and may have an anti-viral effect on nCoV. However, further validation and investigation of these inhibitors against SARS-CoV-2 main protease are needed to claim their candidacy for clinical trials.Communicated by Ramaswamy H. Sarma

Hispidin and Lepidine E: Two Natural Compounds and Folic Acid as Potential Inhibitors of 2019-novel Coronavirus Main Protease (2019- nCoVMpro), Molecular Docking and SAR Study.

2019-nCoVis, a novel coronavirus was isolated and identified in 2019 in the city of Wuhan, China. On February 17, 2020 and according to the World Health Organization, 71, 429 confirmed cases worldwide were identified, among them 2162 new cases were recorded in the last 24 hours. One month later, the confirmed cases jumped to 179111, with 11525 new cases in the last 24 hours, with 7426 total deaths. No drug or vaccine is present at the moment for human and animal coronavirus. The inhibition of 3CL hydrolase enzyme provides a promising therapeutic principle for developing treatments against CoViD-19. The 3CLpro (Mpro) is known for involving in counteracting the host innate immune response. This work presents the inhibitory effect of some natural compounds against 3CL hydrolase enzyme, and explains the main interactions in inhibitor-enzyme complex. Molecular docking study was carried out using Autodock Vina. By screening several molecules, we identified three candidate agents that inhibit the main protease of coronavirus. Hispidin, lepidine E, and folic acid are bound tightly in the enzyme, therefore strong hydrogen bonds have been formed (1.69-1.80Å) with the active site residues. This study provides a possible therapeutic strategy for CoViD-19.