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Since 2020, many compounds have been investigated for their potential use in the treatment of SARS-CoV-2 infection. Among these agents, a huge number of natural products and FDA-approved drugs have been evaluated as potential therapeutics for SARS-CoV-2 using virtual screening and docking studies. However, the identification of the molecular targets involved in viral replication led to the development of rationally designed anti-SARS-CoV-2 agents. Among these targets, the main protease (Mpro) is one of the key enzymes needed in the replication of the virus. The data gleaned from the crystal structures of SARS-CoV-2 Mpro complexes with small-molecule covalent inhibitors has been used in the design and discovery of many highly potent and broad-spectrum Mpro inhibitors. The current review focuses mainly on the covalent type of SARS-CoV-2 Mpro inhibitors. The design, chemistry, and classification of these inhibitors were also in focus. The biological activity of these inhibitors, including their inhibitory activities against Mpro, their antiviral activities, and the SAR studies, were discussed. The review also describes the potential mechanism of the interaction between these inhibitors and the catalytic Cys145 residue in Mpro. Moreover, the binding modes and key binding interactions of these covalent inhibitors were also illustrated. The covalent inhibitors discussed in this review were of diverse chemical nature and origin. Their antiviral activity was mediated mainly by the inhibition of SARS-CoV-2 Mpro, with IC 50 values in the micromolar to the nanomolar range. Many of these inhibitors exhibited broad-spectrum inhibitory activity against the Mpro enzymes of other coronaviruses (SARS-CoV-1 and MERS-CoV). The dual inhibition of the Mpro and PLpro enzymes of SARS-CoV-2 could also provide higher therapeutic benefits than Mpro inhibition. Despite the approval of nirmatrelvir by the FDA, many mutations in the Mpro enzyme of SARS-CoV-2 have been reported. Although some of these mutations did not affect the potency of nirmatrelvir, there is an urgent need to develop a second generation of Mpro inhibitors. We hope that the data summarized in this review could help researchers in the design of a new potent generation of SARS-CoV-2 Mpro inhibitors. [Display omitted] • The classification of the covalent inhibitors of SARS-CoV-2 Mpro was discussed. • The design and/or identification strategies were summarized. • Their antiviral activity, Mpro inhibitory activity, and SAR were described. • The potential mechanisms of the interaction with Cys145 were presented. • The binding modes and interactions of selected inhibitors with Mpro were provided. [ABSTRACT FROM AUTHOR]

Herein, six previously undescribed steroids (1–6), were isolated from leaves and twigs of Aphanamixis polystachya (Wall.) R. N. Parker (Meliaceae). Their structures were elucidated by comprehensive spectroscopic analysis, including HRESIMS, 1D and 2D NMR, UV, and IR. Antiviral activity of these compounds were evaluated. Compounds 1–6 showed varying degrees of inhibitory activity against the severe acute respiratory syndrome coronavirus 2 main protease (SARS-CoV-2 Mpro) at 200 μ M. [Display omitted] [ABSTRACT FROM AUTHOR]

[Display omitted] The escalation of many coronavirus variants accompanied by the lack of an effective cure has motivated the hunt for effective antiviral medicines. In this regard, 18 Saudi Arabian medicinal plants were evaluated for SARS CoV-2 main protease (Mpro) inhibition activity. Among them, Terminalia brownii and Acacia asak alcoholic extracts exhibited significant Mpro inhibition, with inhibition rates of 95.3 % and 95.2 %, respectively, at a concentration of 100 µg/mL. Bioassay-guided phytochemical study for the most active n -butanol fraction of T. brownii led to identification of eleven compounds, including two phenolic acids (1 , and 2), seven hydrolysable tannins (3 – 10), and one flavonoid (11) as well as four flavonoids from A. asak (12 – 15). The structures of the isolated compounds were established using various spectroscopic techniques and comparison with known compounds. To investigate the chemical interactions between the identified compounds and the target Mpro protein, molecular docking was performed using AutoDock 4.2. The findings identified compounds 4 , 5 , 10 , and 14 as the most potential inhibitors of Mpro with binding energies of −9.3, −8.5, −8.1, and −7.8 kcal mol−1, respectively. In order to assess the stability of the protein–ligand complexes, molecular dynamics simulations were conducted for a duration of 100 ns, and various parameters such as RMSD, RMSF, Rg, and SASA were evaluated. All selected compounds 4 , 5 , 10 , and 14 showed considerable Mpro inhibiting activity in vitro , with compound 4 being the most powerful with an IC 50 value of 1.2 µg/mL. MM-GBSA free energy calculations also revealed compound 4 as the most powerful Mpro inhibitor. None of the compounds (4 , 5 , 10 , and 14) display any significant cytotoxic activity against A549 and HUVEC cell lines. [ABSTRACT FROM AUTHOR]

We report the synthesis, biological evaluation, and X-ray structural studies of a series of SARS-CoV-2 Mpro inhibitors based upon the X-ray crystal structure of nirmatrelvir, an FDA approved drug that targets the main protease of SARS-CoV-2. The studies involved examination of various P4 moieties, P1 five- and six-membered lactam rings to improve potency. In particular, the six-membered P1 lactam ring analogs exhibited high SARS-CoV-2 Mpro inhibitory activity. Several compounds effectively blocked SARS-CoV-2 replication in VeroE6 cells. One of these compounds maintained good antiviral activity against variants of concern including Delta and Omicron variants. A high-resolution X-ray crystal structure of an inhibitor bound to SARS-CoV-2 Mpro was determined to gain insight into the ligand-binding properties in the Mpro active site. [Display omitted] • Design and synthesis of potent SARS-CoV-2 Mpro inhibitors are reported. • Inhibitors with a six-membered P1 lactam exhibited improved antiviral activity. • Inhibitors maintained potent antiviral activity against variants of concern. • An inhibitor exhibited improved antiviral profile in immunocytochemistry assays. • The X-ray crystal structure of SARS-CoV-2 Mpro inhibitor complex was determined. [ABSTRACT FROM AUTHOR]

The main protease (Mpro) enzyme has an imperative function in disease progression and the life cycle of the SARS-CoV-2 virus. Although the orally active drug nirmatrelvir (co-administered with ritonavir as paxlovid) has been approved for emergency use as the frontline antiviral agent, there are a number of limitations that necessitate the discovery of new drug scaffolds, such as poor pharmacokinetics and susceptibility to proteolytic degradation due to its peptidomimetic nature. This study utilized a novel virtual screening workflow that combines pharmacophore modelling, multiple-receptor covalent docking, and biological evaluation in order to find new Mpro inhibitors. After filtering and analysing ∼66,000 ligands from three different electrophilic libraries, 29 compounds were shortlisted for experimental testing, and two of them exhibited ≥20% inhibition at 100 μM. Our top candidate, GF04, is a benzylpyrrolyl compound that exhibited the highest inhibition activity of 38.3%, with a relatively small size (<350 Da) and leadlike character. Interestingly, our approach also identified another hit, DR07, a pyrimidoindol with a non-peptide character, and a molecular weight of 438.9 Da, reporting an inhibition of 26.3%. The established approach detailed in this study, in conjunction with the discovered inhibitors, has the capacity to yield novel perspectives for devising covalent inhibitors targeting the COVID-19 Mpro enzyme and other comparable targets. [Display omitted] • A pharmacophore model was successfully constructed for use as a filter in our ligand-based/structure-based workflow. • The pharmacophore filtration-based workflow outperformed the conventional workflow upon AUC comparsion. • Covalent docking based virtual screening was used to find small druglike leads, for biological evaluation. • GF04, a leadlike hit with a benzylpyrrolyl scaffold, reported inhibition at 38.8% against SARS-CoV-2 Mpro enzyme. • DR07, a non-peptide-based lead with a pyrimidoindol scaffold, reported inhibition at 26.3% against SARS-CoV-2 Mpro enzyme. [ABSTRACT FROM AUTHOR]

The COVID-19 pandemic caused by SARS-CoV-2 continues to pose a great threat to public health while various vaccines are available worldwide. Main protease (Mpro) has been validated as an effective anti-COVID-19 drug target. Using medicinal chemistry and rational drug design strategies, we identified a quinazolin-4-one series of nonpeptidic, noncovalent SARS-CoV-2 Mpro inhibitors based on baicalein, 5,6,7-trihydroxy-2-phenyl-4 H -chromen-4-one. In particular, compound C7 exhibits superior inhibitory activity against SARS-CoV-2 Mpro relative to baicalein (IC 50 = 0.085 ± 0.006 and 0.966 ± 0.065 μM, respectively), as well as improved physicochemical and drug metabolism and pharmacokinetics (DMPK) properties. In addition, C7 inhibits viral replication in SARS-CoV-2-infected Vero E6 cells more effectively than baicalein (EC 50 = 1.10 ± 0.12 and 5.15 ± 1.64 μM, respectively) with low cytotoxicity (CC 50 ＞ 50 μM). An X-ray co-crystal structure reveals a non-covalent mechanism of action, and a noncanonical binding mode not observed by baicalein. These results suggest that C7 represents a promising lead for development of more effective SARS-CoV-2 Mpro inhibitors and anti-COVID-19 drugs. [Display omitted] • A quinazolin-4-one series of noncovalent SARS-CoV-2 Mpro inhibitors were identified. • C7 showed better inhibitory potency against SARS-CoV-2 Mpro than baicalein. • C7 showed better cellular antiviral activity than baicalein with low cytotoxicity. • A crystal structure of D8 in Mpro reveals a noncovalent mechanism of action and distinct binding mode. [ABSTRACT FROM AUTHOR]

[Display omitted] The SARS-CoV-2 main protease (Mpro) has been chosen as a conserved molecular target to develop broad-spectrum antiviral drugs. Using molecular docking and molecular dynamics (MD) simulations, a total of 5600 natural compounds available for virtual screening were tested to identify potential inhibitors of SARS-CoV-2 Mpro. As a result, three natural compounds (pentagalloylglucose, malonylawobanin and gnetin E dihydride) were found to be potential inhibitors of SARS-CoV-2, which confirms the theoretical and practical significance of this approach for the design of SARS-CoV-2 inhibitors. [ABSTRACT FROM AUTHOR]

• Supervised learning model was trained to screen 2 million compounds with a test correlation coefficient of R = 0.748 ± 0.044. • In combination of ML model and LIE/FEP calculation, nine compounds were suggested that they could bind well to SARS-CoV-2 Mpro. • The vdW interaction dominates over electrostatic interaction in the ligand-binding process. • The ligands altered the catalytic triad Cys145 - His41 - Asp187. Inhibiting the biological activity of SARS-CoV-2 Mpro can prevent viral replication. In this context, a hybrid approach using knowledge- and physics-based methods was proposed to characterize potential inhibitors for SARS-CoV-2 Mpro. Initially, supervised machine learning (ML) models were trained to predict a ligand-binding affinity of ca. 2 million compounds with the correlation on a test set of R = 0.748 ± 0.044. Atomistic simulations were then used to refine the outcome of the ML model. Using LIE/FEP calculations, nine compounds from the top 100 ML inhibitors were suggested to bind well to the protease with the domination of van der Waals interactions. Furthermore, the binding affinity of these compounds is also higher than that of nirmatrelvir, which was recently approved by the US FDA to treat COVID-19. In addition, the ligands altered the catalytic triad Cys145 - His41 - Asp187, possibly disturbing the biological activity of SARS-CoV-2. [ABSTRACT FROM AUTHOR]

Although antimicrobial resistance before the Covid-19 pandemic is a top priority for global public health, research is already ongoing on novel organic compounds with antimicrobial and antiviral properties in changing medical environments in connection with Covid 19. Thanks to the Biginelli reaction, which allows the synthesis of pyrimidine compounds, blockers of calcium channels, antibodies, antiviral, antimicrobial, anti-inflammatory, or antioxidant therapeutic compounds were investigated. In this paper, we aim to present Biginelli's synthesis, its therapeutic properties, and the structural–functional relationship in the test compounds that allows the synthesis of antimicrobial compounds. Both the DFT and TD-DFT computations of spectral data, molecular orbitals (HOMO, LUMO) analysis, and electrostatic potential (MEP) surfaces are carried out as an add-on to synthetic research. Hirshfeld surface analysis was also used to segregate the different intermolecular hydrogen bonds involved in the molecular packing strength. Natural Bond Orbital (NBO) investigation endorses the existence of intermolecular interactions mediated by lone pair, bonding, and anti-bonding orbitals. The dipole moment, linear polarizability, and first hyperpolarizabilities have been explored as molecular parameters. All findings based on DFT exhibit the best consistency with experimental findings, implying that synthesized molecules are highly stable. To better understand the binding mechanism of the SARS-CoV-2 Mpro, we performed molecular docking, molecular dynamics (MD) simulations, and binding free energy calculations. [ABSTRACT FROM AUTHOR]

In order to discover new dual-active agents, a series of novel Biginelli hybrids (tetrahydropyrimidines) and their ruthenium(II) complexes were synthesized. Newly synthesized compounds were characterized by IR, NMR, and X-ray techniques and investigated for their cytotoxic effect on human cancer cell lines HeLa, LS174, A549, A375, K562 and normal fibroblasts (MRC-5). For further examination of the cytotoxic mechanisms of novel complexes, two of them were chosen for analyzing their effects on the distribution of HeLa cells in the cell cycle phases. The results of the flow cytometry analysis suggest that the proportion of cells in G2/M phase was decreased following the increase of subG1 phase in all treatments. These results confirmed that cells treated with 5b and 5c were induced to undergo apoptotic death. The ruthenium complexes 5a-5d show significant inhibitory potency against SARS-CoV-2 Mpro. Therefore, molecule 5b has significance, while 5e possesses the lowest values of ΔG bind and K i , which are comparable to cinanserin, and hydroxychloroquine. In addition, achieved results will open a new avenue in drug design for more research on the possible therapeutic applications of dual-active Biginelli-based drugs (anticancer-antiviral). Dual-active drugs based on the hybridization concept "one drug curing two diseases" could be a successful tactic in healing patients who have cancer and the virus SARS-CoV-2 at the same time. [Display omitted] [ABSTRACT FROM AUTHOR]

Density Functional Theory (DFT) and Quantitative Structure-Activity Relationship (QSAR) studies were performed on four benzimidazoles (compounds 1–4) and two benzothiazoles (compounds 5 and 6), previously synthesized by our group. The compounds were also investigated for their binding affinity and interactions with the SARS-CoV-2 Mpro (PDB ID: 6LU7) and the human angiotensin-converting enzyme 2 (ACE2) receptor (PDB ID: 6 M18) using a molecular docking approach. Compounds 1, 2, and 3 were found to bind with equal affinity to both targets. Compound 1 showed the highest predictive docking scores, and was further subjected to molecular dynamics (MD) simulation to explain protein stability, ligand properties, and protein–ligand interactions. All compounds were assessed for their structural, physico-chemical, pharmacokinetic, and toxicological properties. Our results suggest that the investigated compounds are potential new drug leads to target SARS-CoV-2. [ABSTRACT FROM AUTHOR]

Background: COVID-19 (Coronavirus Disease-2019) has spread widely around the world and impacted human health for millions. The lack of effective targeted drugs and vaccines forces scientific world to search for new effective antiviral therapeutic drugs. It has reported that flavonoids have potential inhibitory activity on SARS-CoV-2 Mpro and anti-inflammatory properties. Dihydromyricetin, as a flavonol, also has antiviral and anti-inflammatory potential. However, the inhibition of dihydromyricetin on SARS-CoV-2 Mpro and the protective effect of dihydromyricetin on pulmonary inflammation and fibrosis have not been proved and explained.Purpose: The coronavirus main protease (Mpro) is essential for SARS-CoV-2 replication and to be recognized as an attractive drug target, we expect to find the inhibitor of Mpro. Novel coronavirus infection can cause severe inflammation and even sequelae of pulmonary fibrosis in critically ill patients. We hope to find a drug that can not only inhibit virus replication but also alleviate inflammation and pulmonary fibrosis in patients.Methods: FRET-based enzymatic assay was used to evaluate the inhibit activity of dihydromyricetin on SARS-CoV-2 Mpro. Molecular docking was used to identify the binding pose of dihydromyricetin with SARS-CoV-2 Mpro. The protective effects of dihydromyricetin against BLM-induced pulmonary inflammation and fibrosis were investigated in C57BL6 mice. BALF and lung tissue were collected for inflammation cells count, ELISA, masson and HE staining, western blotting and immunohistochemistry to analyze the effects of dihydromyricetin on pulmonary inflammation and fibrosis. MTT, western blotting, reverse transcription-polymerase chain reaction (RT-PCR) and wound healing were used to analyze the effects of dihydromyricetin on lung fibrosis mechanisms in Mlg cells.Results: In this study, we found that dihydromyricetin is a potent inhibitor targeting the SARS-CoV-2 Mpro with a half-maximum inhibitory concentration (IC50) of 1.716 ± 0.419 μM, using molecular docking and the FRET-based enzymatic assay. The binding pose of dihydromyricetin with SARS-CoV-2 Mpro was identified using molecular docking method. In the binding pocket of SARS-CoV-2 Mpro, the dihydrochromone ring of dihydromyricetin interact with the imidazole side chain of His163 through π-π stacking. The 1-oxygen of dihydromyricetin forms a hydrogen bond with the backbone nitrogen of Glu166. The 3-, 7-, 3'- and 4'-hydroxyl of dihydromyricetin interact with Gln189, Leu141, Arg188 and Thr190 through hydrogen bonds. Moreover, our results showed that dihydromyricetin can significantly alleviate BLM-induced pulmonary inflammation by inhibiting the infiltration of inflammation cells and the secretion of inflammation factors in the early process and also ameliorate pulmonary fibrosis by improving pulmonary function and down-regulate the expression of α-SMA and fibronectin in vivo. Our results also showed that dihydromyricetin inhibits the migration and activation of myofibroblasts and extracellular matrix production via transforming growth factor (TGF)-β1/Smad signaling pathways.Conclusion: Dihydromyricetin is an effective inhibitor for SARS-CoV-2 Mpro and it prevents BLM-induced pulmonary inflammation and fibrosis in mice. Dihydromyricetin will be a potential medicine for the treatment of COVID-19 and its sequelae. [ABSTRACT FROM AUTHOR]

The emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) as a novel coronavirus and the etiological agent of global pandemic coronavirus disease (COVID-19) requires quick development of potential therapeutic strategies. Computer aided drug design approaches are highly efficient in identifying promising drug candidates among an available pool of biological active antivirals with safe pharmacokinetics. The main protease (MPro) enzyme of SARS-CoV-2 is considered key in virus production and its crystal structures are available at excellent resolution. This marks the enzyme as a good starting receptor to conduct an extensive structure-based virtual screening (SBVS) of ASINEX antiviral library for the purpose of uncovering valuable hits against SARS-CoV-2 MPro. A compound hit (BBB_26580140) was stand out in the screening process, as opposed to the control, as a potential inhibitor of SARS-CoV-2 MPro based on a combined approach of SBVS, drug likeness and lead likeness annotations, pharmacokinetics, molecular dynamics (MD) simulations, and end point MM-PBSA binding free energy methods. The lead was further used in ligand-based similarity search (LBSS) that found 33 similar compounds from the ChEMBL database. A set of three compounds (SCHEMBL12616233, SCHEMBL18616095, and SCHEMBL20148701), based on their binding affinity for MPro, was selected and analyzed using extensive MD simulation, hydrogen bond profiling, MM-PBSA, and WaterSwap binding free energy techniques. The compounds conformation with MPro show good stability after initial within active cavity moves, a rich intermolecular network of chemical interactions, and reliable relative and absolute binding free energies. Findings of the study suggested the use of BBB_26580140 lead and its similar analogs to be explored in vivo which might pave the path for rational drug discovery against SARS-CoV-2 MPro. [Display omitted] • BBB_26580140 from ASINEX antiviral library is identified as potent hit against SARS-CoV-2 MPro. • The compound is showing stronger affinity for SARS-CoV-2 MPro with respect to carmofur control. • SCHEMBL12616233, SCHEMBL18616095 and SCHEMBL20148701 analogs are good SARS-CoV-2 MPro binders. • Analogs are produce rich chemical interactions and acquire equilibrium with SARS-CoV-2 MPro. [ABSTRACT FROM AUTHOR]

• Four Azo imidazole derivatives (L1-L4) have been synthesized and characterized by different spectroscopic and analytical tools. • The inhibitory potential of the derivatives (L1-L4) against main protease (Mpro, 6LU7) have been investigated using computational techniques. • Molecular docking results showed that the derivatives (L1-L4) could act as potential inhibitor against the protein 6LU7 of SARS-CoV-2. • Binding energy (ΔG) values of the ligands (L1-L4) against the protein 6LU7 have found to be −7.7 Kcal/mole (L1), −7.0 Kcal/mole (L2), −7.9 Kcal/mole (L3) and 7.9 Kcal/mole (L4). • Pharmacokinetic properties of the derivatives (L1-L4) have also been investigated using SWISSADME program. Four novel ionic liquid tagged azo-azomethine derivatives (L1-L4) have been prepared by the condensation reaction of azo-coupled ortho-vaniline precursor with amino functionalised imidazole derivative and the synthesized derivatives (L1-L4) have been characterized by different analytical and spectroscopic techniques. Molecular docking studies were carried out to ascertain the inhibitory action of studied ligands (L1-L4) against the Main Protease (6LU7) of novel coronavisrus (COVID-19). The result of the docking of L1-L4 showed a significant inhibitory action against the Main protease (Mpro) of SARS-CoV-2 and the binding energy (ΔG) values of the ligands (L1-L4) against the protein 6LU7 have found to be −7.7 Kcal/mole (L1), −7.0 Kcal/mole (L2), −7.9 Kcal/mole (L3), and −7.9 Kcal/mole (L4).The efficiency of the ligands has been compared with the FDA approved and clinically trial drugs such as remdesivir, Chloroquin and Hydroxychloroquin and native ligand N3 of main protease 6LU7 to ascertain the inhibitory potential of the studied ligands (L1-L4) against the protein 6LU7. Pharmacokinetic properties (ADME) of the ligands (L1-L4) have also been studied. Image, graphical abstract [ABSTRACT FROM AUTHOR]

The COVID-19 pandemic raised by SARS-CoV-2 is a public health emergency. However, lack of antiviral drugs and vaccine against human coronaviruses demands a concerted approach to challenge the SARS-CoV-2 infection. Under limited resource and urgency, combinatorial computational approaches to identify the potential inhibitor from known drugs could be applied against risen COVID-19 pandemic. Thereof, this study attempted to purpose the potent inhibitors from the approved drug pool against SARS-CoV-2 main protease (Mpro). To circumvent the issue of lead compound from available drugs as antivirals, antibiotics with broad spectrum of viral activity, i.e. doxycycline, tetracycline, demeclocycline, and minocycline were chosen for molecular simulation analysis against native ligand N3 inhibitor in SARS-CoV-2 Mpro crystal structure. Molecular docking simulation predicted the docking score >−7 kcal/mol with significant intermolecular interaction at the catalytic dyad (His41 and Cys145) and other essential substrate binding residues of SARS-CoV-2 Mpro. The best ligand conformations were further studied for complex stability and intermolecular interaction profiling with respect to time under 100 ns classical molecular dynamics simulation, established the significant stability and interactions of selected antibiotics by comparison to N3 inhibitor. Based on combinatorial molecular simulation analysis, doxycycline and minocycline were selected as potent inhibitor against SARS-CoV-2 Mpro which can used in combinational therapy against SARS-CoV-2 infection. Unlabelled Image • Docking predicted docking score > −7 kcal/mol for tetracyclines with SARS-CoV-2 Mpro. • Tetracyclines showed interactions with Mpro active pocket residues. • Protease-tetracyclines stability was monitored by 100 ns MD simulation. • Doxycycline and minocycline were predicted as potent SARS-CoV-2 Mpro inhibitors. [ABSTRACT FROM AUTHOR]

A new SARS coronavirus (SARS-CoV-2) belonging to the genus Betacoronavirus has caused a pandemic known as COVID-19. Among coronaviruses, the main protease (Mpro) is an essential drug target which, along with papain-like proteases catalyzes the processing of polyproteins translated from viral RNA and recognizes specific cleavage sites. There are no human proteases with similar cleavage specificity and therefore, inhibitors are highly likely to be nontoxic. Therefore, targeting the SARS-CoV-2 Mpro enzyme with small molecules can block viral replication. The present study is aimed at the identification of promising lead molecules for SARS-CoV-2 Mpro enzyme through virtual screening of antiviral compounds from plants. The binding affinity of selected small drug-like molecules to SARS-CoV-2 Mpro, SARS-CoV Mpro and MERS-CoV Mpro were studied using molecular docking. Bonducellpin D was identified as the best lead molecule which shows higher binding affinity (−9.28 kcal/mol) as compared to the control (−8.24 kcal/mol). The molecular binding was stabilized through four hydrogen bonds with Glu166 and Thr190 as well as hydrophobic interactions via eight residues. The SARS-CoV-2 Mpro shows identities of 96.08% and 50.65% to that of SARS-CoV Mpro and MERS-CoV Mpro respectively at the sequence level. At the structural level, the root mean square deviation (RMSD) between SARS-CoV-2 Mpro and SARS-CoV Mpro was found to be 0.517 Å and 0.817 Å between SARS-CoV-2 Mpro and MERS-CoV Mpro. Bonducellpin D exhibited broad-spectrum inhibition potential against SARS-CoV Mpro and MERS-CoV Mpro and therefore is a promising drug candidate, which needs further validations through in vitro and in vivo studies. [ABSTRACT FROM AUTHOR]