COVID-19 Main Protease Inhibitors Research Articles

Computational Approaches Molecular Docking and MD Simulation Establishes the Potential COVID-19 Main Protease Inhibitors from Natural Products

Aim: COVID-19 was classified as a pandemic by the World Health Organization (WHO) on March 11, 2020. No reliable cure, however, was found. To prevent viral replication, complementary therapy with antiviral and antimalarial medications were used. However, due to their synthetic origin, they have a lot of side effects. To overcome this bane natural origin drugs were repositioned. Background: As repositioned drugs do not undergo a pro-long process of pre-clinical trial, hence, they play an excellent role in the spillover of pathogens. The main protease (6LU7) enzyme found in severe acute respiratory syndrome coronavirus-2 (SAR-CoV-2) is essential for viral replication. Thus, it acts as a hotspot in drug discovery. Objective: A molecular docking computational approach was used to determine the ability of the binding contract between the selected 3D-models of COVID-19 protease target and proposed natural compounds pristimerin, amazoquinone, kendomycin, celastrol, 20-epi-isoguesterinol, phenanthrenequinone, taxodione, maytenoquinone, hippeastrine, ammothamnine, 28-hydroxy isoiguesterin, hemanthamine, alisol-B, stigmasterol, β-pinene,and β-sitosterol through Autodock v.1.5.6 software. Method: The present study is designed to perform in-silico studies using molecular docking (Autodock tool v.1.5.6), Discovery Studio 2017 R2 client, Patch dock, SWISS-ADME prediction, and molecular simulation (Desmond simulation package of Schrodinger) between 6LU7 and natural origin compounds. Result: The results of docking study performed between 6LU7 and compounds pristimerin, amazoquinone, kendomycin, celastrol, 20-epi-isoguesterinol, phenanthrenequinone, taxodione, maytenoquinone, hippeastrine, ammothamnine, 28-hydroxy isoiguesterin, hemanthamine, alisol-B, stigmasterol, β-pinene, and β-sitosterol, showed binding energy as -9.68, -7.34, -5.34, -4.63, -4.24, -4.13, -4.08, -3.85, -3.83, -3.7, -3.6, -3.57, -3.54, -3.39, -3.18, and -3.03 Kcal/mol, respectively. It can be shown that the Pristimerin-6LU7 protein complex was maintained throughout the simulation since the ligand RMSDs varied with a maximum value of 4.2Å during the first 10 ns, followed by more stable interactions for the remaining time of the simulation. Conclusion: The goal of the current work was to find inhibitors for both prophylactic and therapeutic usage in COVID-19 patients.

A novel pyrazole derivative as COVID-19 main protease inhibitor: Synthesis, quantum computational studies, pharmacokinetic properties, drug likeness, molecular docking and dynamics simulation; a CADD approach

2-(3‑bromo-1-(3-chloropyridin-2-yl)-1H-pyrazol-5-yl)-8-methyl-4H benzo[d][1,3]oxazin-4-one (2-BCBO) compound, was synthesized by the reaction of 3‑bromo-1-(3-chloropyridin-2-yl)-1H-pyrazole-5-carboxylic acid in acetonitrile and methane sulfonyl chloride. The monoclinic crystal structure in C2/c space group of the compound was unveiled through single-crystal X-ray diffraction studies. A prediction model was employed to investigate the influence of intermolecular contacts on molecular packing in the crystalline phase. The model incorporated both Hirshfeld surface and 2D fingerprint models to gain a comprehensive understanding of the strength of these contacts. The calculation of the total interaction energy was conducted by utilizing the three-dimensional molecular energy frameworks and further, employed density functional theory to examine molecular orbital characteristics and key factors associated with chemical reactivity. The application of topological analysis techniques, such as QTAIM and NCI, provided further insight regarding the attraction and repulsive interactions shown by the molecule. The pharmacokinetic properties of the 2-BCBO molecule have also been examined using ADMET analysis, which is important in drug discovery and development. In addition, the molecular docking study to determine the inhibitory effect of the investigated ligand on the main protease of new coronavirus (COVID-19), followed by molecular dynamics simulations, and it is found that both the results are in good agreement. The 2-BCBO could be accepted as a lead molecule to treat the coronavirus.

A Molecular Generative Model of COVID-19 Main Protease Inhibitors Using Long Short-Term Memory-Based Recurrent Neural Network.

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused a serious threat to public health and prompted researchers to find anti-coronavirus 2019 (COVID-19) compounds. In this study, the long short-term memory-based recurrent neural network was used to generate new inhibitors for the coronavirus. First, the model was trained to generate drug compounds in the form of valid simplified molecular-input line-entry system strings. Then, the structures of COVID-19 main protease inhibitors were applied to fine-tune the model. After fine-tuning, the network could generate new molecular structures as novel SARS-CoV-2 main protease inhibitors. Molecular docking exhibited that some generated compounds have the proper affinity to the active site of the protease. Molecular Dynamics simulations explored binding free energies of the compounds over simulation trajectories. In addition, in silico absorption, distribution, metabolism, and excretion studies showed that some novel compounds could be formulated as orally active agents. Based on molecular docking and molecular dynamics simulation studies, compound AADH possessed significant binding affinity and presumably inhibition against the SARS-CoV-2 main protease enzyme. Therefore, the proposed deep learning-based model was capable of generating promising anti-COVID-19 drugs.

Synthesis, DFT, ADME and docking studies of Homoegonol and Egonol as potential inhibitors of COVID-19 main protease (6LU7)

To produce Homoegonol and Egonol with high yields via a divergent synthetic method, we describe a novel and simple synthesis strategy. This method, which makes use of the adaptable Heck reaction, starts with commercially available 2-hydroxy-3-methoxybenzaldehyde, (3,4-dimethoxy-phenyl)methanol, and (benzo[d][1,3]dioxol-5-yl)methanol. When synthesising these important molecules, our approach offers improved efficiency, simplicity, and ease. The chemical structures of all the newly synthesized intermediates and products were elucidated by their IR, 1H &13C NMR and mass spectral data. Further DFT calculation was carried out at B3LYP/6–31 g++(d,p) level theory. ADME analysis represents synthesized drugs that show oral bioavailability and drug-like nature. Docking studies carried out against 6LU7, docking results represent the good interaction with Egonol and Homoegonol, binding energy is −10.16 kcal/mol for both Homoegonol and egonol.

Investigation of Methyl-5-(pentan-3-yloxy)-7-oxabicyclo[4.1.0]hept-3-ene-3-carboxyhydrazide Derivatives as Potential Inhibitors of COVID-19 Main Protease: DFT and Molecular Docking Study.

The search for effective therapeutics to combat COVID-19 has led to the exploration of the biological activity of numerous compounds. In this study, hydrazones derived from oseltamivir intermediate, methyl 5-(pentan-3-yloxy)-7-oxabicyclo[4.1.0]hept-3-ene-3-carboxylate have been investigated for their potential as drug candidates against the COVID-19 virus using computational methods, including density functional theory (DFT) studies, molecular docking, and absorption, distribution, metabolism, excretion and toxicity (ADMET) analysis. The DFT studies provide information on the electronic properties of the compounds while the molecular docking results using AutoDock reported the binding energies between the main protease of COVID-19 and the compounds. The DFT results revealed that the energy gap of the compounds ranged from 4.32 to 5.82 eV while compound HC had the highest energy gap (5.82 eV) and chemical potential (2.90 eV). The electrophilicity index values of the 11 compounds ranged from 2.49 to 3.86, thus they were classified as strong electrophiles. The molecular electrostatic potential (MESP) revealed electron-rich and electron-deficient regions of the compounds. The docking results reveal that all the compounds had better docking scores than remdesivir and chloroquine, frontline drugs employed in combating COVID-19, with HC having the best docking score of -6.5. The results were visualized using Discovery studio, which revealed hydrogen bonding, pi-alkyl interaction, alkyl interaction, salt bridge interaction, halogen interaction as being responsible for the docking scores. The drug-likeness results showed that the compounds qualify as oral drug candidates as none of them violated Vebers and Lipinski's rule. Thus, they could serve as potential inhibitors of COVID-19.

Identification of potent COVID-19 main protease inhibitors by loading of favipiravir on Mg12O12 and Zn12O12 nanoclusters: an in silico strategy for COVID-19 treatment

Pandemic new severe acute respiratory syndrome coronavirus (SARS-CoV-2) virus has increased throughout the world. There is no effective treatment against this virus until now. Since its appearance in Wuhan, China in December 2019, SARS-CoV-2 becomes the largest challenge the world is opposite today, including the discovery of an antiviral drug for this virus. Several viral proteins have been prioritized as SARS-CoV-2 antiviral drug targets, among them the papain-like protease (PLpro) and the main protease (Mpro). Inhibition of these proteases would target viral replication, viral maturation and suppression of host innate immune responses. Potential candidates have been identified to show inhibitory effects against Mpro, both in biochemical assays and viral replication in cells. There are different molecules such as lopinavir and favipiravir considerably inhibit the activity of Mpro in vitro. Different studies have shown that structurally improved favipiravir and other similar compounds can inhibit SARS-CoV-2 main protease. In this work, we study the interactions between favipiravir with Mg12O12 and Zn12O12 nanoclusters by density functional theory (DFT) and quantum mechanics atoms in molecules (QMAIM) methods to summarize the ability to load favipiravir onto Mg12O12 and Zn12O12 nanoclusters. Favipiravir-Mg12O12 and favipiravir-Zn12O12 lowest structures complexes were chosen to dock inside the SARS-CoV-2 main protease by molecular docking study. The molecular docking analysis revealed that the binding affinity of Mg12O12 and Zn12O12 nanoclusters inside the Mpro receptor is larger than that of favipiravir. Also, the loading of favipiravir on the surface of Mg12O12 and Zn12O12 nanoclusters increased the binding affinity against the Mpro receptor. Subsequently, 100 ns molecular dynamics simulation of the favipiravir-Mg12O12, and favipiravir-Zn12O12 docked inside the Mpro complexes established that favipiravir-Mg12O12, forms the most stable complex with the Mpro. Further molecular mechanics Poisson Boltzmann surface area (MMPBSA) analyses using the MD trajectories also demonstrated the higher binding affinity of favipiravir-Mg12O12 inside the Mpro. In summary, this study demonstrates a new way to characterize leads for novel anti-viral drugs against SARS-CoV-2, by improving the drug ability of favipiravir via loading it on Mg12O12 and Zn12O12 nanoclusters. Communicated by Ramaswamy H. Sarma

Zeolite A/ZnCl2 nanoparticles as a catalyst for eco-friendly synthesis of pyrazole-1- carbothioamides with docking validation as Covid-19 main protease (MPRO) inhibitor

ABSTRACT. The synthesized Zeolite A/ZnCl2 nanoparticles via the hydrothermal route were characterized using FTIR, XRD, and SEM/EDAX techniques. The characterized catalyst was used for the eco-friendly synthesis of 4,5-dihydro-pyrazole-1-carbothioamide derivatives. Under solvent-free conditions, a multi-component reaction between hydrazine, isothiocyanate, and chalcone was done with a prepared nano-catalyst as an inexpensive, recyclable, easy-to-get, and nontoxic catalyst. The molecular docking study explained that dihydro-1-carbothioamide pyrazoles can be considered COVID-19 main protease (Mpro) inhibitors. In order to investigate the 3D conformation of the compounds that were synthesized, the density functional theory (DFT) was applied with a B3LYP hybrid functional and a 6-311++ G(d,p) basis set. This allowed us to investigate the compounds' electronic and charge transfer properties. In this series of compounds, the derivative 30d showed the lowest HOMO–LUMO energy gap.
 
 KEY WORDS: Zeolite A/ZnCl2 nanoparticles, Pyrazole-1-carbothioamides, Docking, XRD, SEM/EDX, HRTEM
 
 Bull. Chem. Soc. Ethiop. 2023, 37(2), 391-404. 
 DOI: https://dx.doi.org/10.4314/bcse.v37i2.11

Computational molecular docking and in silico ADMET prediction studies of pyrazole derivatives as Covid-19 main protease (MPRO) and papain-like protease (PLPRO) inhibitors

ABSTRACT. The inhibition of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) main protease (Mpro) and papain-like protease (PLpro) prevents viral multiplications. Molecular docking, absorption, distribution, metabolism, excretion, and toxicity (ADMET) studies of pyrazole-indole molecules 6a, b, Schiff bases 8a, b, and pyrazolo[1,5-a]pyrimidines 10a, b were performed and done. Based on the molecular docking study verified that the presented structures (6a, 6b, 8a, 8b, 10a, and 10b) give promised attached bonds with the active site in the COVID-19 main protease (Mpro). The results of in silico ADMET prediction study revealed that these compounds may be considered candidates for the discovery or development of new series of COVID-19 drugs.
 
 KEY WORDS: Pyrazole, Fused pyrazole, Schiff bases, COVID-19, Molecular docking, Computational studies
 
 Bull. Chem. Soc. Ethiop. 2023, 37(2), 449-461. 
 DOI: https://dx.doi.org/10.4314/bcse.v37i2.14

Insight into designing of 2-pyridone derivatives for COVID-19 drug discovery - A computational study.

Presently, the prime global focus is on SARS-CoV-2, as no fully established, licensed medicine has been found thus far, in spite of the existence of various reports and administration of partially proven certain class of natural products. However, in case of natural products, the extraction and purification limit their application. This situation drives researchers to explore synthetically viable drugs. In the present investigation, twenty-three 2-pyridone synthetic derivatives (P1-P23) have been theoretically tested for their suitability as potential inhibitors for COVID-19 main protease through DFT, molecular docking, and molecular dynamics simulations. DFT calculations offer insights into structure–property relationships, while ADMET studies indicate the pharmacological characteristics of these molecules. Molecular docking studies ascertain the nature and mode of interactions of these entities with COVID-19 main protease. Furthermore, covalent docking has been carried out to verify the feasibility of the formation of a covalent bond with the active site. The top protein-inhibitor complexes, such as P18, P11, and P12, were identified based on their glide score. These molecules, along with the covalent docked complexes, namely P18 and P16, were selected and subjected to molecular dynamics simulations. The 100 ns simulation process exhibited that the covalent docked ones, due to their stable form could serve as lead compounds against SARS-CoV-2. Hence, this study affirms the potential candidature of 2-pyridone-based inhibitors.

Screening, molecular simulation &in silico kinetics of virtually designed covid-19 main protease inhibitors

Coronavirus (covid-19) infection is considered to be deadliest ever pandemic experienced by the human being. It has very badly affected the socio-economic health of human and stuck the scientific community to think and rethink about its complete eradication. But due to no effective treatment or unavailability of vaccine the health professional could not show any significant improvement to control the pandemic. The situation needs newer molecule, vaccine or effective treatment to control covid-19 infection. Different target in viruses has been explored and proteases enzymes were found to be therapeutically effective target for the design of potential anti-covid-19 molecule as it plays the vital role in viral replication and assembly. Structure-based drug design was employed to discover the small molecule of anti-covid-19. Here we considered the small library of naturally occurring polyphenolic compounds and molecular docking, Molecular dynamics (MD) simulations, free binding energy calculation and in-silico ADME calculations to identify the newer HITs. Based upon their score the two molecules were identified as promising candidate. The docking scores were found to be −7.643 and −7.065 for the HIT1 and HIT-2 respectively. In MD simulations study the RMSD values were found to be 4.3 Å & 4.9 Å respectively. To validate these results MM-GBSA was performed and their binding free energies were computationally determined. The prime energy values of identified HITs (−13412.45 & −13441.8 kJ/mole) were found to be very close proximity to reference molecule (−13493.05 kJ/mole). Then in-silico ADME calculations were performed to calculate the drug likeliness identified HITs. BY considering all the values comparative to reference molecule and obtained in-silico pharmacokinetic properties of identified HITs we can suggest that HIT-1 and HIT-2 would be the most promising molecules that can inhibit the main protease enzyme of covid-19. These two molecules would become the potential drug candidate for the treatment of covid-19 infections.

SAR and QSAR of COVID-19 Main Protease–Inhibitor Interactions of Recently X-ray Crystalized Complexes

COVID-19 is still widespread worldwide and up to now there is no established antiviral able to control the disease. Main protease is responsible for the viral replication and transcription; thus, its inhibition is a promising route to control virus proliferation. The present study aims to examine detail interactions between main protease and recently reported ninety-seven inhibitors with available X-ray crystallography to define factors enhance inhibition activity; thirty-two of most potent inhibitors were examined to identify sites and types of interaction. The study showed formation of covalent bond, H-bond and hydrophobic interaction with key residues in the active side. Covalent bond is observed in seventeen complexes, all of them by attack of the 145Cys thiol group on Michael acceptor, aldehyde or its hydrate, α-ketoamide, double bond or acetamide methyl group; the latter type requires H-bonding between acetamide carbonyl oxygen and at least one of 143Gly, 144Ser or 145Cys. Potent inhibitors, disulfiram and ebselen docked in the same binding site. Accordingly, factors identify inhibition include forming covalent bond and existing terminal hydrophobic groups and amidic or peptidomimetic structure. Binding affinity was found correlated with topological diameter up to 24 bond, molecular size, branching, polar surface area up to 199 Å2 and hydrophilicity.Supplementary InformationThe online version contains supplementary material available at 10.1007/s40011-021-01338-8.

Exploration of plant-derived natural polyphenols toward COVID-19 main protease inhibitors: DFT, molecular docking approach, and molecular dynamics simulations.

Recent outbreaks of coronavirus have brought serious challenges to public health around the world, and it is essential to find effective treatments. In this study, the 3C-like proteinase (3CLpro) of SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2) has been considered as an important drug target because of its role in viral replication. We initially optimized 251 compounds at the PM7 level of theory for docking with 3CLpro, and then we selected the top 12 compounds for further optimization with the B3LYP-D3/6-311G** method and obtained the top four compounds by further molecular docking. Quantum chemistry calculations were performed to predict molecular properties, such as the electrostatic potential and some CDFT descriptors. We also performed molecular dynamics simulations and free energy calculations to determine the relative stability of the selected four potential compounds. We have identified key residues controlling the 3CLpro/ligand binding from per-residue based decomposition of the binding free energy. Convincingly, the comprehensive results support the conclusion that the compounds have the potential to become a candidate for anti-coronavirus treatment.

Repurposing drug molecule against SARS-Cov-2 (COVID-19) through molecular docking and dynamics: a quick approach to pick FDA-approved drugs.

A novel coronavirus known as severe acute respiratory syndrome is rapidly spreading worldwide. The international health authorities are putting all their efforts on quick diagnosis and placing the patients in quarantine. Although different vaccines have come for quick use as prophylactics, drug repurposing seems to be of paramount importance because of inefficient therapeutic options and clinical trial limitations. Here, we used structure-based drug designing approach to find and check the efficacy of the possible drug that can inhibit coronavirus main protease which is involved in polypeptide processing to functional protein. We performed virtual screening, molecular docking and molecular dynamics simulations of the FDA-approved drugs against the main protease of SARS-CoV-2. Using well-defined computational methods, we identified amprenavir, cefoperazone, riboflavin, diosmin, nadide and troxerutin approved for human therapeutic uses, as COVID-19 main protease inhibitors. These drugs bind to the SARS-CoV-2 main protease conserved residues of substrate-binding pocket and formed a remarkable number of non-covalent interactions. We have found diosmin as an inhibitor which binds covalently to the COVID-19 main protease. This study provides enough evidences for therapeutic use of these drugs in controlling COVID-19 after experimental validation and clinical demonstration.Graphical abstract Supplementary InformationThe online version contains supplementary material available at 10.1007/s00894-021-04923-w.

Synthesis of New Binary Thiazole-Based Heterocycles and Their Molecular Docking Study as COVID-19 Main Protease (Mpro) Inhibitors.

Isolated polynuclear binary heterocyclic compounds containing thiazole building block combined with benzofuran, pyrrole, thiazole, or thiophene via carboxamide and/or secondary amine as a junction are presented. The synthetic strategy of those is based on utilization of 2-chloroacetamido-4-phenylthiazole in the synthesis of binary heterocyclic compounds by cyclocondensation with salicylic aldehyde, acetonitrile derivatives, ammonium thiocyanate, 3-mercaptoacrylonitrile derivatives, and/or 3-mercaptoacrylate derivatives. The prepared binary thiazole-based heterocycles have been studied as protease (Mpro) inhibitors by molecular docking for visualization of their orientation and interactions with COVID-19 units using hydroxychloroquine as a reference molecule.

Computational Identification of SARS-CoV-2 Inhibitor in Tinospora cordifolia, Cinnamomum zeylanicum and Myristica fragrans.

A novel coronavirus disease (COVID-19), caused by SARS-CoV-2, has spread over more than 100 countries all over the world. The World Health Organization has recognized Coronavirus as a pandemic and finding an effective drug for this infectious disease is of high importance. In this study, we have explored the potent inhibitors of COVID-19 main protease from Tinospora cordifolia an Ayurvedic herb locally called as Amrita meaning ‘immortality’ and two other Ayurveda plants namely Cinnamomum zeylanicum and Myristica fragrans. Saponarin, a phytochemical present in Tinospora cordifolia showed a very promising result with the binding affinity of − 8.75 kcal/mol. Remdesivir and Favipiravir, the experimental drugs that are known to show inhibitory activity towards COVID-19 are used as a control. The Docking results were verified by the means of molecular dynamic analysis. This study suggests that Saponarin can be a potential inhibitor for the main protease of the COVID-19.

Docking-based virtual screening and identification of potential COVID-19 main protease inhibitors from brown algae

COVID-19 (SARS-CoV-2) is a viral disease that causes acute respiratory syndrome, which has increased the morbidity and mortality rate throughout the world. World Health Organization has declared this COVID-19 outbreak as pandemic and classified health emergency throughout the world. In the recent past, outbreaks of SARS and MERS have shown the interspecies transmission potential of coronaviruses and limitations of already prescribed drugs to overcome this global public health issue. Therefore, there is a dire need to identify a new regimen of targeted drugs from natural compounds having anti-COVID19 potential. This study aimed at screening 1018 brown algal natural compounds (many of them previously reported to have immunomodulatory effects) having probable anti-COVID19 potentials. The source compounds were extracted from MarinLit, a database dedicated to marine natural products and screened against COVID-19 main protease. The top seven compounds were further analysed, and their interactions with the active site were visualized. This study will further warrant screening the potent compounds against the virus in-vitro conditions.

Copper-based glass-ceramic as an efficient catalyst in the synthesis of pyrazolo[1,5-a] pyrimidineunder solvent-free condition with docking validation as Covid-19 main protease (Mpro) inhibitor

Copper-based oxide glass-ceramic was successfully synthesized through the single-step melt annealing technique. Synthesized glass-ceramics was characterized using X-ray diffraction (XRD) and scanning electron microscopy (SEM) supported with energy dispersive X-ray (EDX) and mapping. Pyrazolo[1,5-a]pyrimidines 5a-f were synthesized via the reaction of 5-amino-1H-pyrazole-4-carboxamide (1) with enaminones 2a-f in the presence of synthesized oxide glass-ceramic catalyst powder under solvent-free condition. The molecular docking study demonstrated that the COVID-19 main protease (MPro) inhibitor.
 
 KEY WORDS: Pyrazolopyrimidine, Enaminones, Copper-based catalysis, Solvent-free, COVID-19
 
 Bull. Chem. Soc. Ethiop. 2021, 35(1), 185-196.
 DOI: https://dx.doi.org/10.4314/bcse.v35i1.16

Discovery of potent Covid-19 main protease inhibitors using integrated drug-repurposing strategy.

The emergence and rapid spreading of novel SARS‐CoV‐2 across the globe represent an imminent threat to public health. Novel antiviral therapies are urgently needed to overcome this pandemic. Given the significant role of the main protease of Covid‐19 for virus replication, we performed a drug‐repurposing study using the recently deposited main protease structure, 6LU7. For instance, pharmacophore‐ and e‐pharmacophore‐based hypotheses such as AARRH and AARR, respectively, were developed using available small molecule inhibitors and utilized in the screening of the DrugBank repository. Further, a hierarchical docking protocol was implemented with the support of the Glide algorithm. The resultant compounds were then examined for their binding free energy against the main protease of Covid‐19 by means of the Prime‐MM/GBSA algorithm. Most importantly, the machine learning‐based AutoQSAR algorithm was used to predict the antiviral activities of resultant compounds. The hit molecules were also examined for their drug‐likeness and toxicity parameters through the QikProp algorithm. Finally, the hit compounds activity against the main protease was validated using molecular dynamics simulation studies. Overall, the present analysis yielded two potential inhibitors (DB02986 and DB08573) that are predicted to bind with the main protease of Covid‐19 better than currently used drug molecules such as N3 (cocrystallized native ligand), lopinavir, and ritonavir.

Extracts of Mesua Ferrea Linn, the natural Inhibitors of COVID-19 main protease: a computational quest

The coronavirus, known as severe acute respiratory syndrome (SARS-CoV-2), is accountable for the global epidemic disease COVID-19. The effective treatment of this disease is still unknown and there is an emergent need to use all resources to find the effective medication. The use of off-label natural medicinal compounds may be effective remedy for this scourge. Towards the investigation of effective inhibitor of 3CL protease, we studied the in silico interaction of the selected compounds of Mesua Ferrae Linn, an Asian medicinal plant. The studied compounds have shown excellent inhibition properties. The timber extracts, Mesuabixanthone-B (∆Gbind = -15.51 kcal/mol) and Mesuferrol-B (∆Gbind = -14.32 kcal/mol) are among the exciting hits on 6LU7. The in silico prediction of toxicities of the extracts are also promising. The further lab research is necessary to testify these drug candidates against COVID-19 infections.

Natural products as inhibitors of COVID-19 main protease–A virtual screening by molecular docking

Background: The novel coronavirus (2019-nCoV) causes a severe respiratory illness unknown to a human before. Its alarmingly quick transmission to many countries across the world has resulted in a global health emergency. Therefore, an imminent need for drugs to combat this disease has been increased. Worldwide collaborative efforts from scientists are underway to determine a therapy to treat COVID-19 infections and reduce mortality rates. Since herbal medicines and purified natural products have been reported to have antiviral activity against Coronaviruses (CoVs), this in silico evaluation was performed for identifying potential natural compounds with promising inhibitory activities against COVID-19. Methods: In this study, a High Throughput Virtual Screening (HTVS) protocol was used as a fast method for discovering novel drug candidates as potential COVID-19 main protease (Mpro) inhibitors. Over 180,000 natural product-based compounds were obtained from the ZINC database and virtually screened against the COVID-19 Mpro. In this study, the Glide docking program was applied for high throughput virtual screening. Also, Extra precision (XP) has been used following the induced-fit docking (IFD) approach. The ADME properties of all compounds were analyzed and a final selection was made based on the Lipinski rule of five. Also, molecular dynamics (MD) simulations were conducted for a virtual complex of the best scoring compound with COVID-19 protease. Results: Nineteen compounds were introduced as new potential inhibitors. Compound ZINC08765174 (1-[3-(1H-indol-3-yl) propanoyl]-N-(4-phenylbutan-2-yl)piperidine-3-carboxamide showed a strong binding affinity (-11.5 kcal/mol) to the COVID-19 Mpro comparing to peramivir (-9.8 kcal/mol) as a positive control. Conclusions: Based on these findings, nineteen compounds were proposed as possible new COVID-19 inhibitors, of which ZINC08765174 had a high affinity to Mpro. Furthermore, the promising ADME properties of the selected compounds emphasize their potential as attractive candidates for the treatments of COVID-19.