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Viral infections cause significant health problems all over the world, and it is critical to develop treatments for these problems. Antivirals that target viral genome-encoded proteins frequently cause the virus to become more resistant to treatment. Because viruses rely on several cellular proteins and phosphorylation processes that are essential to their life cycle, drugs targeting host-based targets could be a viable treatment option. To reduce costs and improve efficiency, existing kinase inhibitors could be repurposed as antiviral medications; however, this method rarely works, and specific biophysical approaches are required in the field. Because of the widespread use of FDA-approved kinase inhibitors, it is now possible to better understand how host kinases contribute to viral infection. The purpose of this article is to investigate the tyrphostin AG879 (Tyrosine kinase inhibitor) binding information in Bovine Serum Albumin (BSA), human ErbB2 (HER2), C-RAF1 Kinase (c-RAF), SARS-CoV-2 main protease (COVID 19), and Angiotensin-converting enzyme 2 (ACE-2).Communicated by Ramaswamy H. Sarma.

COVID-19, the disease responsible for the recent pandemic, is caused by a novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The main protease (Mpro) of SARS-CoV-2 is an essential proteolytic enzyme that plays a number of important roles in the replication of the virus in human host cells. Blocking the function of SARS-CoV-2 Mpro offers a promising and targeted, therapeutic option for the treatment of the COVID-19 infection. Such an inhibitory strategy is currently successful in treating COVID-19 under FDA's emergency use authorization, although with limited benefit to the immunocompromised along with an unfortunate number of side effects and drug-drug interactions. Current COVID vaccines protect against severe disease and death but are mostly ineffective toward long COVID which has been seen in 5-36% of patients. SARS-CoV-2 is a rapidly mutating virus and is here to stay endemically. Hence, alternate therapeutics to treat SARS-CoV-2 infections are still needed. Moreover, because of the high degree of conservation of Mpro among different coronaviruses, any newly developed antiviral agents should better prepare us for potential future epidemics or pandemics. In this paper, we first describe the design and computational docking of a library of novel 188 first-generation peptidomimetic protease inhibitors using various electrophilic warheads with aza-peptide epoxides, α-ketoesters, and β-diketones identified as the most effective. Second-generation designs, 192 compounds in total, focused on aza-peptide epoxides with drug-like properties, incorporating dipeptidyl backbones and heterocyclic ring motifs such as proline, indole, and pyrrole groups, yielding 8 hit candidates. These novel and specific inhibitors for SARS-CoV-2 Mpro can ultimately serve as valuable alternate and broad-spectrum antivirals against COVID-19.Communicated by Ramaswamy H. Sarma.

Ligand-based drug design methods are thought to require large experimental datasets to become useful for virtual screening. In this work, we propose a computational strategy to design novel inhibitors of coronavirus main protease, M pro . The pipeline integrates publicly available screening and binding affinity data in a two-stage machine-learning model using the recent MACAW embeddings. Once trained, the model can be deployed to rapidly screen large libraries of molecules in silico . Several hundred thousand compounds were virtually screened and 10 of them were selected for experimental testing. From these 10 compounds, 8 showed a clear inhibitory effect on recombinant M pro , with half-maximal inhibitory concentration values (IC 50 ) in the range 0.18-18.82 μM. Cellular assays were also conducted to evaluate cytotoxic, haemolytic, and antiviral properties. A promising lead compound against coronavirus M pro was identified with dose-dependent inhibition of virus infectivity and minimal toxicity on human MRC-5 cells.

In the current pandemic caused by the new coronavirus (SARS-CoV-2), computational drug discovery can play an essential role in finding potential therapeutic agents. Thanks to its anti-viral, antibacterial, and anti-inflammatory properties, sage ( Salvia officinalis ) is used in traditional medicine. In this study, drugs proposed against COVID-19, including Lopinavir, Remdesivir, Favipiravir, and main flavonoids of sage, were docked favorably against novel coronavirus main protease. Molecular docking findings indicate that Rutin, Luteolin-7-glucoside, Apigenin, and Hispidulin make strong interactions with better binding affinity than selected commercial drugs in the study. But Rutin is the only flavonoid that makes strong hydrogen bond interactions with catalytic dyad and crucial M pro residues and has more binding affinity than protease inhibitor PF-07321332 as an oral antiviral (PAXLOVID™). Further analysis of Molecular Dynamics and MM-PBSA predicted that chosen ligands could form stable complexes with the main protease. Also, ADMET analysis shows that main flavonoids are expected to have appropriate pharmacokinetic and no toxic properties. The results of the in silico study suggest that Salvia officinalis as a rich source of potent anti-coronavirus flavonoids may play a significant role in counteracting the replication of SARS-CoV-2.Communicated by Ramaswamy H. Sarma.

The COVID-19 is declared a pandemic by World Health Organization (WHO). It causes respiratory illness which leads to oxygen deficiency; it has affected millions of lives all around the globe. It has also been observed that people with diabetes condition are more likely to have severe symptoms when infected with the SARS-CoV2. So, continued efforts are being taken to design and discover potential anti-covid drugs. Earlier, a study reveals that the acetonitrile (2-phenyl-4H-benzopyrimedo [2,1-b]-thiazol-4-yliden) derivatives have potential anti-diabetic activity. Hence, drugs repurpose approach was used to identify the potential acetonitrile derivative targeting the main protease of SARS-CoV2. Here, ADMET, molecular docking, and molecular dynamics simulation techniques were employed, to identify potential acetonitrile compounds against the main protease. The acetonitrile compounds (A to M) show the drug-likeness properties. Next, the molecular docking and dynamics simulation study reveals that acetonitrile compounds A, F, G, and L show a higher binding affinity and have an effect on the structure and dynamics of the main protease. Furthermore, binding energy calculations reveal that the acetonitrile derivative F has a higher binding affinity with the main protease and derivative L has a lower binding affinity with the main protease. The binding affinity of acetonitrile derivatives decreases in the order of F > A > G > L with the main protease. Thus, our computational modeling study provides valuable structural and energetic information of interaction of potential acetonitrile derivatives with the main protease which could be further used as potential lead molecules against the SARS-CoV2.Communicated by Ramaswamy H. Sarma.

Main protease (M pro ) is a critical enzyme in the life cycle of severe acute respiratory syndrome Coronavirus -2 (SARS-CoV-2). Due to its essential role in the maturation of the polyproteins, the necessity to inhibit M pro is one of the essential means to prevent the outbreak of COVID-19. In this context, this study was conducted on the natural compounds of medicinal plants that are commonly available in the Middle East to find out the most potent one to inhibit M pro with the best bioavailability and druglikeness properties. A total of 3392 compounds of sixty-six medicinal plants were retrieved from PubChem database and docked against M pro . Thirty compounds with the highest docking scores with M pro were chosen for further virtual screening. Variable druglikeness and toxicity potentials of these compounds were evaluated using SwissADME and Protox servers respectively. Out of these virtually screened compounds, artecanin was predicted to exhibit the most favourable druglikeness potentials, accompanied by no predicted hepatoxicity, carcinogenicity, mutagenicity, and cytotoxicity. Molecular dynamics (MD) simulations showed that M pro -artecanin complex exhibited comparable stability with that observed in the ligand-free M pro . This study revealed for the first time that artecanin from Laurus nobilis provided a novel static and dynamic inhibition for M pro with excellent safety, oral bioavailability, and pharmacokinetic profile. This study suggested the ability of artecanin to be used as a potential natural inhibitor that can be used to block or at least counteract the SARS-CoV-2 invasion.Communicated by Ramaswamy H. Sarma.

SARS-CoV-2, a new coronavirus emerged in 2019, causing a global healthcare epidemic. Although a variety of drug targets have been identified as potential antiviral therapies, and effective candidate against SARS-CoV-2 remains elusive. One of the most promising targets for combating COVID-19 is SARS-CoV-2 Main protease (M pro , a protein responsible for viral replication. In this work, an in-house curated library was thoroughly evaluated for druggability against M pro . We identified four ligands (FG, Q5, P5, and PJ4) as potential inhibitors based on docking scores, predicted binding energies (MMGBSA), in silico ADME, and RMSD trajectory analysis. Among the selected ligands, FG, a natural product from Andrographis nallamalayana, exhibited the highest binding energy of -10.31 kcal/mol close to the docking score of clinical candidates Boceprevir and GC376. Other ligands (P5, natural product from cardiospermum halicacabum and two synthetic molecules Q5 and PJ4) have shown comparable docking scores ranging -7.65 kcal/mol to -7.18 kcal/mol. Interestingly, we found all four top ligands had Pi bond interaction with the main amino acid residues HIS41 and CYS145 (catalytic dyad), H-bonding interactions with GLU166, ARG188, and GLN189, and hydrophobic interactions with MET49 and MET165 in the binding site of M pro . According to the ADME analysis, Q5 and P5 are within the acceptable range of drug likeliness, compared to FG and PJ4. The interaction stability of the lead molecules with viral protease was verified using replicated MD simulations. Thus, the present study opens up the opportunity of developing drug candidates targeting SARS-CoV-2 main protease (M pro ) to mitigate the disease.Communicated by Ramaswamy H. Sarma.

The global outbreak of the COVID-19 pandemic provokes scientists to make a prompt development of new effective therapeutic interventions for the battle against SARS-CoV-2. A new series of N -(5-nitrothiazol-2-yl)-carboxamido derivatives were designed and synthesised based on the structural optimisation principle of the SARS-CoV Mpro co-crystallized WR1 inhibitor. Notably, compound 3b achieved the most promising anti-SARS-CoV-2 activity with an IC 50 value of 174.7 µg/mL. On the other hand, compounds 3a , 3b , and 3c showed very promising SARS-CoV-2 Mpro inhibitory effects with IC 50 values of 4.67, 5.12, and 11.90 µg/mL, respectively. Compound 3b docking score was very promising (-6.94 kcal/mol) and its binding mode was nearly similar to that of WR1. Besides, the molecular dynamics (MD) simulations of compound 3b showed its great stability inside the binding pocket until around 40 ns. Finally, a very promising SAR was concluded to help to design more powerful SARS-CoV-2 Mpro inhibitors shortly.

Despite a huge effort by the scientific community to determine the animal reservoir of SARS-CoV-2, which led to the identification of several SARS-CoV-2-related viruses both in bats and in pangolins, the origin of SARS-CoV-2 is still not clear. Recently, Temmam et al. reported the discovery of bat coronaviruses with a high degree of genome similarity with SARS-CoV-2, especially concerning the RBDs of the S protein, which mediates the capability of such viruses to enter and therefore infect human cells through a hACE2-dependent pathway. These viruses, especially the one named BANAL-236, showed a higher affinity for the hACE2 compared to the original strain of SARS-CoV-2. In the present work, we analyse the similarities and differences between the 3CL protease (main protease, M pro ) of these newly reported viruses and SARS-CoV-2, discussing their relevance relative to the efficacy of existing therapeutic approaches against COVID-19, particularly concerning the recently approved orally available Paxlovid, and the development of future ones.

The recent outbreak of COVID-19 caused by a new human coronavirus called SARS-CoV-2, is continually causing worldwide human infections and deaths.The main protease (3CLpro), which plays a critical role in the life cycle of the virus, makes it an attractive target for the development of antiviral agents effective against coronaviruses (CoVs).Currently, there is no specific viral protein targeted therapeutics.Therefore, there is a need to investigate an alternative therapy which will prevent the spread of the infection, by focusing on the transmission of the virus.Chlorhexidine (CHX) and flavonoids agents have shown that they have a viral inactivation effect against enveloped viruses, and thus facilitate the struggle against oral transmission.Especially, some flavonoids have very strong antiviral activity in SARS-CoV and MERS-CoV main protease.This study was conducted to evaluate the CHX and flavonoids compounds potential antiviral effects on SARS-CoV-2 main protease through virtual screening for the COVID-19 treatment by molecular docking method.According to the results of this study, CHX, Kaempferol-3-rutinoside, Rutin, Quercetin 3-beta-D-glucoside and Isobavachalcone exhibited the best binding affinity against this enzyme, and also these compounds showed significant inhibitory effects compared to the SARS-CoV-2 main protease crystal structure inhibitor (N3).Especially, these compounds mainly interact with His41, Cys145, His163, Met165, Glu166 and Thr190 in SARS-CoV-2 main protease binding site. Further, MD simulation analysis also confirmed that stability of these interactions between the enzyme and these five compounds.The current study provides to guide clinical trials for broad-spectrum CHX and bioactive flavonoids to reduce the viral load of the infection and possibly disease progression.Communicated by Ramaswamy H. Sarma.

A respiratory pandemic known as coronavirus disease-19 (COVID-19) has created havoc since it emerged from Wuhan, China. COVID-19 is caused by a newly emerged SARS coronavirus (SARS-CoV) with increased pathogenicity named severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2). Due to the lack of understanding of the mechanism of pathogenesis, an effective therapeutic option is unavailable. Epidemics described in Unani ancient literature include nazla-e-wabai and humma-e-wabai , and most of the symptoms of COVID-19 resemble nazla-e-wabai . Hence, in light of Unani literature, the treatment of COVID-19 can be managed with the composites prescribed in Unani medicine for nazla-e-wabai . In this study, a structure-based drug design approach was carried out to check the effectiveness of the pharmacologically active constituents of the Unani composites prescribed to treat nazla-e-wabai against SARS-CoV-2. We performed molecular docking of the active constituents of these composites against the main protease (M pro ), a potential drug target in SARS-CoV-2. Using detailed molecular docking analysis, Habb-ul-aas and Tabasheer were identified as potential inhibitors of SARS-CoV-2 M pro . The active constituents of both these composites bind to the substrate-binding pocket of SARS-CoV-2 M pro , forming interactions with key residues of the binding pocket. Molecular dynamics (MD) simulation suggested the binding of active constituents of Habb-ul-aas with SARS-CoV-2 M pro with a strong affinity as compared to the constituents of Tabasheer. Thus, this study sheds light on the use of these Unani composites in COVID-19 therapeutics.Communicated by Ramaswamy H. Sarma.

Drug repurposing requires a limited resource, cost-effective and faster method to combat severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Therefore, this in silico studies attempts to identify the drug-likeness properties of ravidasvir, an II/III phase clinical trial chronic hepatitis C drug against 3-Chymotrypsin-like protease (3CL pro ) of SARS-CoV-2 to combat the ongoing coronavirus disease 2019 (COVID-19) pandemic. This protease is predominantly involved in virus replication cycle; hence it is considered as a potent drug target. The molecular docking results showed that ravidasvir was found to be potent inhibitors of 3CL pro with scoring function based binding energy is -26.7 kJ/mol. Further dynamic behaviour of apo form and complex form of ravidasvir with 3CL pro were studied using molecular dynamics (MD) simulations over 500 ns each, total 2 µs time scale. The motion of the protein was studied using principal component analysis of the MD simulation trajectories. The binding free energy calculated using MM/PBSA method from the MD simulation trajectory was -190.3 ± 70.2 kJ/mol and -106.0 ± 26.7 kJ/mol for GROMOS96 54A7 and AMBER99SB-ILDN force field, respectively. This in silico studies suggesting ravidasvir might be a potential lead molecule against SARS-CoV-2 for further optimization and drug development to combat the life-threatening COVID-19 pandemic.Communicated by Ramaswamy H. Sarma.

COVID-19 also known as SARS-CoV-2 outbreak in late 2019 and its worldwide pandemic spread has taken the world by surprise. The minute-to-minute increasing coronavirus cases (>85 M) and progressive deaths (≈1.8 M) calls for finding a cure to this devastating pandemic. While there have been many attempts to find biologically active molecules targeting SARS-CoV-2 for treatment of this viral infection, none has found a way to the clinic yet. In this study, a 3-feature structure-based pharmacophore model was designed for SARS-CoV-2 main protease (M Pro ) that plays a vital role in the viral cellular penetration. High throughput virtual screening of the lead-like ZINC library was then performed to find a potent inhibitor employing the predesigned pharmacophore. In-silico pharmacokinetics/toxicity prediction study was subsequently applied towards the best hits. Finally, a 50 ns molecular dynamics simulation was carried out for the best hit and compared to the co-crystallized ligand where the hit compound displayed high binding and comparable interactions. The results identified new hits for SARS-CoV-2 M Pro inhibition showing good docking score, pharmacokinetics and toxicity profile, drug-likeness, high binding energy in addition to a promising synthetic accessibility. Identifying new small compounds as potential leads for inhibiting SARS-CoV-2 is a very important step towards designing a synthesizing of promising drug candidates.Communicated by Ramaswamy H. Sarma.

Coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is a rapidly growing health care emergency across the world. One of the viral proteases called main protease or Mpro, plays a crucial role in the replication of SARS-CoV-2. As the structure of Mpro of SARS-CoV-2 is similar to the Mpro of SARS-CoV-1 (responsible for SARS outbreak between 2002 and 2004), we hypothesize that the inhibitors of SARS-CoV-1 Mpro can also inhibit the Mpro of SARS-CoV-2. To test this hypothesis, a total of 79 isatin derivatives, which inhibited Mpro activity under in vitro conditions, were selected from the literature, and then screened through AutoDock Vina. The chemical features of the top 5 isatin derivatives with low binding energies (-8.5 to -8.2 kcal/mol) were used to screen similar types of compounds from several small-molecule libraries containing 15856508 compounds. A total of 1,609 compounds with similarity score ≥ 6 were screened and then subjected to docking as well as ADME analysis. Among the compounds screened, 4 ligands form Zinc drug-like library (ZINC000008848565, ZINC000009513563, ZINC000036759789 and ZINC000046053855) showed good ADMET properties, low binding energy (-8.4 to -8.6 kcal/mol), low interaction energy (-72.62 to -50.01 kcal/mol) and high structural stability with Mpro. Hence, the selected ligands might serve as the lead candidates for further wet laboratory validation, optimization and development.Communicated by Ramaswamy H. Sarma.

In response to the current pandemic caused by the novel SARS-CoV-2, we design new compounds based on Lopinavir structure as an FDA-approved antiviral agent which is currently under more evaluation in clinical trials for COVID-19 patients. This is the first example of the preparation of Lopinavir isosteres from the main core of Lopinavir conducted to various heterocyclic fragments. It is proposed that main protease inhibitors play an important role in the cycle life of coronavirus. Thus, the protease inhibition effect of synthesized compounds was studied by molecular docking method. All of these 10 molecules, showing a good docking score compared. Molecular dynamics (MD) simulations also confirmed the stability of the best-designed compound in Mpro active site.Communicated by Ramaswamy H. Sarma.

Coronavirus disease 2019 (COVID-19) has created a global human health crisis and economic setbacks. Lack of specific therapeutics and limited treatment options against COVID-19 has become a new challenge to identify potential hits in order to develop new therapeutics. One of the crucial life cycle enzymes of SARS-CoV-2 is main protease (M pro ), which plays a major role in mediating viral replication, makes it an attractive drug target. Virtual screening and three times repeated 100 ns molecular dynamics simulation of the best hits were performed to identify potential SARS-CoV-2 M pro inhibitors from the available compounds of an antiviral plant Moringa oleifera. Three flavonoids isorhamnetin ( 1 ), kaempferol ( 2 ) and apigenin ( 3 ) showed good binding affinity, stable protein-ligand complexes throughout the simulation time, high binding energy and similar binding poses in comparison with known SARS-CoV-2 M pro inhibitor baicalein. Therefore, different parts of M. oleifera may be emerged as a potential preventive and therapeutic against COVID-19.

The outbreak of the second severe acute respiratory syndrome coronavirus (SARS-CoV-2) known as COVID-19 has caused global concern. No effective vaccine or treatment to control the virus has been approved yet. Social distancing and precautionary protocols are still the only way to prevent person-to-person transmission. We hope to identify anti-COVID-19 activity of the existing drugs to overcome this pandemic as soon as possible. The present study used HEX and AutoDock Vina softwares to predict the affinity of about 100 medicinal structures toward the active site of 3-chymotrypsin-like protease (3Clpro) and RNA-dependent RNA polymerase (RdRp), separately. Afterwards, MOE software and the pharmacophore-derived query methodology were employed to determine the pharmacophore model of their inhibitors. Tegobuvir ( 19 ) and compound 45 showed the best binding affinity toward RdRp and 3Clpro of SARS-CoV-2 in silico, respectively. Tegobuvir -previously applied for hepatitis C virus- formed highly stable complex with uncommon binding pocket of RdRp (E total: -707.91 Kcal/mol) in silico. In addition to compound 45 , tipranavir ( 28 ) and atazanavir ( 26 ) as FDA-approved HIV protease inhibitors were tightly interacted with the active site of SARS-CoV-2 main protease as well. Based on pharmacophore modelling, a good structural pattern for potent candidates against SARS-CoV-2 main enzymes is suggested. Re-tasking or taking inspiration from the structures of tegobuvir and tipranavir can be a proper approach toward coping with the COVID-19 in the shortest possible time and at the lowest cost.Communicated by Ramaswamy H. Sarma.

The global pandemic due to the novel Severe Acute Respiratory Syndrome Corona Virus 2 (SARS-CoV-2) has taken more than a million lives. Lack of definitive vaccine/drugs against this highly contagious virus has accelerated exploratory research on novel natural and synthetic inhibitors. Tea is a rich source of bioactives and known to have antiviral properties. In this study, an in silico strategy involving ADMET property screening, receptor-ligand docking and molecular dynamic (MD) simulation was employed to screen potential tea bio-active inhibitors against three selected targets (RdRp, 3CLpro and PLpro) of SARS-CoV-2. Among the 70 tea bioactives screened, theaflavin 3,3'-di-gallate (TF3), Procyanidin B2 and Theaflavin 3-gallate (TF2a) exhibited highest binding affinities towards RdRp, 3CLpro/Mpro and PLpro targets of SARS-CoV-2 with low docking scores of -14.92, -11.68 and -10.90 kcal/mol, respectively. All of them showed a substantial number of hydrogen bonds along with other interactions in and around the active sites. Interestingly, the top bioactives in our study showed higher binding affinities compared with known antiviral drugs. Further, the top protein-ligand complexes showed less conformational changes during binding when subjected to MD simulation for 100 nanoseconds. The MMPBSA results revealed that RdRp-TF3, 3CLpro-Procyanidin B2 and PLpro-TF2a complexes were stable with binding free energies of -93.59 ± 43.97, -139.78 ± 16.51 and -96.88 ± 25.39 kJ/mol, respectively. Our results suggest that theaflavin 3,3'-digallate, Theaflavin 3-gallate and Procyanidin B2 found in black tea have the potential to act as inhibitors for selected targets of SARS-CoV-2 and can be considered as drug candidates in future studies against COVID-19.

Currently, no antiviral drug or vaccine is available to treat COVID-19 caused by SARS-CoV-2. This underscores an urgent need for developing a drug against SARS-CoV-2. The main protease (3CL pro ) of SARS-CoV-2 is considered an essential protein for maintaining the viral life cycle and, therefore, a potential target for drug development. In a recent study, 1000 potential ligands were identified for 3CL pro by screening 1.3 billion compounds from the ZINC15 library. In the current study, we have further screened these 1000 compounds using structure-based virtual screening utilizing the Schrödinger suite and identified nine compounds having a docking score of ∼ -11.0 kcal/mol or less. The top 5 hits display good pharmacological profiles revealing better absorption, proper permeability across the membrane, uniform distribution, and non-toxic. The molecular docking study is further complemented by molecular dynamics simulations of the top 5 docked complexes. The binding free energy analyses via the molecular mechanics generalized Born surface area (MM/GBSA) scheme reveals that ZINC000452260308 is the most potent (ΔG bind = -14.31 kcal/mol) inhibitor. The intermolecular van der Waals interactions mainly drive the 3CL pro -ligand association. This new compound may have great potential as a lead molecule to develop a new antiviral drug to fight against COVID-19.Communicated by Ramaswamy H. Sarma.

Repurposing of antivirals is an attractive therapeutic option for the treatment of COVID-19. Main protease (M pro ) , also called 3 C-like protease (3CL pro ) is a key protease of SARS-CoV-2 involved in viral replication, and is a promising drug target for antivirals. A major challenge to test the efficacy of antivirals is the conformational plasticity of M pro and its future mutation prone flexibility. Suitable choice of drugs in catalytic and allosteric pockets appear to be essential for combination therapy. Current study, based on docking and extensive set of MD simulations, finds the combination of Elbasvir, Glecaprevir and Ritonavir to be a viable candidate for further experimental drug testing/pharmacophore design for M pro .Communicated by Ramaswamy H. Sarma.

COVID-19 caused by a positive-sense single stranded RNA virus named as severe acute respiratory syndrome-Coronavirus-2 (SARS-CoV-2) triggered the global pandemic. This virus has infected about 10.37 Crores and taken lives of 2.24 Crores people of 213 countries to date. To cope-up this emergency clinical trials are undergoing with some existing drugs like remdesivir, flavipiravir, lopinavir-ritonavir, nafamostat, doxycycline, hydroxy-chloroquine, dexamethasone, etc., despite their severe toxicity and health hazards among diabetics, hypertensive, cardiac patients or normal individuals. The lack of safe and approved treatment for COVID-19 has forced the scientific community to find novel and safe compounds with potential efficacy. This study evaluates a few selective herbal compounds like glucoraphanin, vitexin, niazinin, etc., as a potential inhibitor of the spike protein and 3-chymotrypsin-like protease (3CLpro) or main protease (Mpro) of SARS-COV-2 through in-silico virtual studies such as molecular docking, target analysis, toxicity prediction and ADME prediction and supported by a Molecular-Dynamic simulation. Selective phytocompounds were docked successfully in the binding site of spike glycoprotein and 3CLpro (Mpro) of SARS-CoV-2. In-silico approaches also predict this molecule to have good solubility, pharmacodynamic property and target accuracy through MD simulation and ADME studies. These hit molecules niazinin, vitexin, glucoraphanin also obey Lipinski's rule along with their stable binding towards target protein of the virus, which makes them suitable for further biochemical and cell-based assays followed by clinical investigations to highlight their potential use in COVID-19 treatment.Communicated by Ramaswamy H. Sarma.

In recent times, computational methods played an important role in the down selection of chemical compounds, which could be a potential drug candidate with a high affinity to target proteins. However, the screening methodologies, including docking, often fails to identify the most effective compound, which could be a ligand for the target protein. To solve that, here we have integrated meta-dynamics, an enhanced sampling molecular simulation method, with all-atom molecular dynamics to determine a specific compound that could target the main protease of novel severe acute respiratory syndrome coronavirus 2 (SARS-COV-2). This combined computational approach uses the enhanced sampling to explore the free energy surface associated with the protein's binding site (including the ligand) in an explicit solvent. We have implemented this method to find new chemical entities that exhibit high specificity of binding to the 3-chymotrypsin-like cysteine protease (3CLpro) present in the SARS-CoV-2 and segregated to the most strongly bound ligands based on free energy and scoring functions (defined and implemented) from a set of 17 ligands which were prescreened for synthesizability and druggability. Additionally, we have compared these 17 ligands' affinities against controls, N3 and 13b α-ketoamide inhibitors, for which experimental crystal structures are available. Based on our results and analysis from the combined molecular simulation approach, we could identify the best compound which could be further taken as a potential candidate for experimental validation.Communicated by Ramaswamy H. Sarma.

Coronavirus disease-2019 (COVID-19) was firstly reported in Wuhan, China, towards the end of 2019, and emerged as a pandemic. The spread and lethality rates of the COVID-19 have ignited studies that focus on the development of therapeutics for either treatment or prophylaxis purposes. In parallel, drug repurposing studies have also come into prominence. Herein, we aimed at having a holistic understanding of conformational and dynamical changes induced by an experimentally characterized inhibitor on main protease (M pro ) which would enable the discovery of novel inhibitors. To this end, we performed molecular dynamics simulations using crystal structures of apo and α -ketoamide 13b-bound M pro homodimer. Analysis of trajectories pertaining to apo M pro revealed a new target site, which is located at the homodimer interface, next to the catalytic dyad. Thereafter, we performed ensemble-based virtual screening by exploiting the ZINC and DrugBank databases and identified three candidate molecules, namely eluxadoline, diosmin, and ZINC02948810 that could invoke local and global conformational rearrangements which were also elicited by α -ketoamide 13b on the catalytic dyad of M pro. Furthermore, ZINC23881687 stably interacted with catalytically important residues Glu166 and Ser1 and the target site throughout the simulation. However, it gave positive binding energy, presumably, due to displaying higher flexibility that might dominate the entropic term, which is not included in the MM-PBSA method. Finally, ZINC20425029, whose mode of action was different, modulated dynamical properties of catalytically important residue, Ala285. As such, this study presents valuable findings that might be used in the development of novel therapeutics against M pro. Communicated by Ramaswamy H. Sarma.

2020 will be remembered worldwide for the outbreak of Coronavirus disease (COVID-19), which quickly spread until it was declared as a global pandemic. The main protease (Mpro) of SARS-CoV-2, a key enzyme in coronavirus, represents an attractive pharmacological target for inhibition of SARS-CoV-2 replication. Here, we evaluated whether the anti-inflammatory drug Ibuprofen, may act as a potential SARS-CoV-2 Mpro inhibitor, using an in silico study. From molecular dynamics (MD) simulations, we also evaluated the influence of ionic strength on the affinity and stability of the Ibuprofen-Mpro complexes. The docking analysis shows that R(-)Ibuprofen and S(+)Ibuprofen isomers can interact with multiple key residues of the main protease, through hydrophobic interactions and hydrogen bonds, with favourable binding energies (-6.2 and -5.7 kcal/mol, respectively). MM-GBSA and MM-PBSA calculations confirm the affinity of these complexes, in terms of binding energies. It also demonstrates that the ionic strength modifies significantly their binding affinities. Different structural parameters calculated from the MD simulations (120 ns) reveal that these complexes are conformational stable in the different conditions analysed. In this context, the results suggest that the condition 2 (0.25 NaCl) bind more tightly the Ibuprofen to Mpro than the others conditions. From the frustration analysis, we could characterize two important regions (Cys44-Pro52 and Linker loop) of this protein involved in the interaction with Ibuprofen. In conclusion, our findings allow us to propose that racemic mixtures of the Ibuprofen enantiomers might be a potential treatment option against SARS-CoV-2 Mpro. However, further research is necessary to determinate their possible medicinal use.Communicated by Ramaswamy H. Sarma.

The severe acute respiratory syndrome COVID-19 declared as a global pandemic by the World Health Organization has become the present wellbeing worry to the whole world. There is an emergent need to search for possible medications. Cressa cretica is reported to show antitubercular, antibacterial and expectorant property. In this research, we aim to prospect the COVID-19 main protease crystal structure (M pro ; PDB ID: 6LU7) and the active chemical constituents from Cressa cretica in order to understand the structural basis of their interactions. We examined the binding potential of active constituents of Cressa cretica plant to immensely conserved protein M pro of SARS-CoV-2 followed by exploration of the vast conformational space of protein-ligand complexes by molecular dynamics (MD) simulations. The results suggest the effectiveness of 3,5-Dicaffeoylquinic acid and Quercetin against standard drug Remdesivir. The active chemical constituents exhibited good docking scores, and interacts with binding site residues of M pro by forming hydrogen bond and hydrophobic interactions. 3,5-Dicaffeoylquinic acid showed the best affinity towards M pro receptor which is one of the target enzymes required by SARS CoV-2 virus for replication suggesting it to be a novel research molecule. The potential of the active chemical constituents from Cressa cretica against the SARS-CoV-2 virus has best been highlighted through this study. Therefore, these chemical entities can be further scrutinized and provides direction for further consideration for in-vivo and in-vitro validations for the treatment of covid-19. Communicated by Ramaswamy H. Sarma.

The severe acute respiratory syndrome coronavirus-2 (SARS CoV-2) is β-coronavirus that is responsible for the pandemic coronavirus disease 2019 (COVID-19) all over the world. The rapid spread of the novel SARS CoV-2 worldwide is raising a significant global public health issue with nearly 61.86 million people infected and 1.4 million deaths. To date, no specific drugs are available for the treatment of COVID-19. The inhibition of proteases essential for the proteolytic treatment of viral polyproteins is a conventional therapeutic strategy for conquering viral infections. In the study, molecular docking approach was used to screen potential drug compounds among the phytochemicals of Vitex negundo L. against COVID-19 infection. Molecular docking analysis showed that oleanolic acid forms a stable complex and other phyto-compounds ursolic acid, 3β-acetoxyolean-12-en-27-oic acid and isovitexin of V. negundo natural compounds form a less-stable complex. When compared with the control the synergistic interaction of these compounds shows inhibitory activity against papain-like protease (PL pro ) of SARS CoV-2 (COVID-19). The molecular dynamics (MD) simulation (50 ns) were performed on the complexes of PL pro and the phyto-compounds viz . oleanolic acid, ursolic acid, 3β-acetoxyolean-12-en-27-oic acid and isovitexin followed by the binding free energy calculations using MM-GBSA and these molecules have stable interactions with PL pro protein binding site. The MD simulation study provides more insight into the functional properties of the protein-ligand complex and suggests that these molecules can be considered as a potential drug molecule against COVID-19. In this pandemic situation, these herbal compounds provide a rich resource to produce new antivirals against COVID-19.Communicated by Ramaswamy H. Sarma.

The acute respiratory syndrome caused by the SARS-CoV-2, known as COVID-19, has been ruthlessly tormenting the world population for more than six months. However, so far no effective drug or vaccine against this plague have emerged yet, despite the huge effort in course by researchers and pharmaceutical companies worldwide. Willing to contribute with this fight to defeat COVID-19, we performed a virtual screening study on a library containing Food and Drug Administration (FDA) approved drugs, in a search for molecules capable of hitting three main molecular targets of SARS-CoV-2 currently available in the Protein Data Bank (PDB). Our results were refined with further molecular dynamics (MD) simulations and MM-PBSA calculations and pointed to 7 multi-target hits which we propose here for experimental evaluation and repurposing as potential drugs against COVID-19. Additional rounds of docking, MD simulations and MM-PBSA calculations with remdesivir suggested that this compound can also work as a multi-target drug against SARS-CoV-2.Communicated by Ramaswamy H. Sarma.

The recent outbreak of SARS-CoV-2 has quickly become a worldwide pandemic and generated panic threats for both the human population and the global economy. The unavailability of effective vaccines or drugs has enforced researchers to hunt for a potential drug to combat this virus. Plant-derived phytocompounds are of applicable interest in the search for novel drugs. Bioflavonoids from Rhus succedanea are already reported to exert antiviral activity against RNA viruses. SARS-CoV-2 Mpro protease plays a vital role in viral replication and therefore can be considered as a promising target for drug development. A computational approach has been employed to search for promising potent bioflavonoids from Rhus succedanea against SARS-CoV-2 Mpro protease. Binding affinities and binding modes between the biflavonoids and Mpro enzyme suggest that all six biflavonoids exhibit possible interaction with the Mpro catalytic site (-19.47 to -27.04 kcal/mol). However, Amentoflavone (-27.04 kcal/mol) and Agathisflavone (-25.87 kcal/mol) interact strongly with the catalytic residues. Molecular dynamic simulations (100 ns) further revealed that these two biflavonoids complexes with the Mpro enzyme are highly stable and are of less conformational fluctuations. Also, the hydrophobic and hydrophilic surface mapping on the Mpro structure as well as biflavonoids were utilized for the further lead optimization process. Altogether, our findings showed that these natural biflavonoids can be utilized as promising SARS-CoV-2 Mpro inhibitors and thus, the computational approach provides an initial footstep towards experimental studies in in vitro and in vivo , which is necessary for the therapeutic development of novel and safe drugs to control SARS-CoV-2. Communicated by Ramaswamy H. SarmaResearch highlights Rhus succedanea biflavonoids have antiviral activity.The molecular interactions and molecular dynamics displayed that all six biflavonoids bound with a good affinity to the same catalytic site of Mpro.The compound Amentoflavone has a strong binding affinity (-27.0441 kcal/mol) towards Mpro.The binding site properties of SARS-CoV-2-Mpro can be utilized in a novel discovery and lead optimization of the SARS-CoV-2-Mpro inhibitor.

Introduction: The main cysteine protease from SARS-CoV-2 (M pro ), conserved among many pathogenic coronaviruses, represents a recently validated antiviral drug target, with at least one inhibitor recently approved for clinical use as an antiviral drug, nirmatrelvir (paxlovid TM )., Areas Covered: The authors review the scientific literature on the drug design landscape of α-ketoamide SARS-CoV-2 M pro inhibitors. The X-ray/neutron crystal structure of three such compounds is available, which has allowed for drug design rationalization. The α-ketoamide functionality of the inhibitors reacts with the catalytic dyad cysteine residue to form a hemithioketal. The S3, S2, and S1' subsites of the protease are filled with various aromatic or aliphatic (cyclic/acyclic) moieties of the peptidomimetic, whereas in S1, the preferred moiety was a rigid 2-pyrrolidone or norvaline side chain (as in telaprevir)., Expert Opinion: Crystallography, previous drug design efforts, and many computational studies have allowed for a deeper understanding of the structural requirements needed for designing effective SARS-CoV-2 M pro α-ketoamide inhibitors. However, all the reported derivatives are peptidomimetics with a rather high molecular weight. It is expected that effective compounds with lower molecular weights and a lesser peptidomimetic profile will be the target for future drug development.

The COVID-19 pandemic has claimed more than a million lives worldwide within a short time span. Due to the unavailability of specific antiviral drugs or vaccine, the infections are causing panic both in general public and among healthcare providers. Therefore, an urgent discovery and development of effective antiviral drug for the treatment of COVID-19 is highly desired. Targeting the main protease (M pro ) of the causative agent, SARS-CoV-2 has great potential for drug discovery and drug repurposing efforts. Published crystal structures of SARS-CoV-2 M pro further facilitated in silico investigations for discovering new inhibitors against M pro . The present study aimed to screen several libraries of synthetic flavonoids and benzisothiazolinones as potential SARS-CoV-2 M pro inhibitors using in silico methods. The short-listed compounds after virtual screening were filtered through SwissADME modeling tool to remove molecules with unfavorable pharmacokinetics and medicinal properties. The drug-like molecules were further subjected to iterative docking for the identification of top binders of SARS-CoV-2 M pro . Finally, molecular dynamic (MD) simulations and binding free energy calculations were performed for the evaluation of the dynamic behavior, stability of protein-ligand complex, and binding affinity, resulting in the identification of thioflavonol, TF-9 as a potential inhibitor of M pro . The computational studies further revealed the binding of TF-9 close to catalytic dyad and interactions with conserved residues in the S1 subsite of the substrate binding site. Our in-silico study demonstrated that synthetic analogs of flavonoids, particularly thioflavonols, have a strong tendency to inhibit the main protease M pro , and thereby inhibit the reproduction of SARS-CoV-2. Communicated by Ramaswamy H. Sarma.

COVID-19 pandemic has created a healthcare crisis across the world and has put human life under life-threatening circumstances. The recent discovery of the crystallized structure of the main protease (M pro ) from SARS-CoV-2 has provided an opportunity for utilizing computational tools as an effective method for drug discovery. Targeting viral replication has remained an effective strategy for drug development. M pro of SARS-COV-2 is the key protein in viral replication as it is involved in the processing of polyproteins to various structural and nonstructural proteins. Thus, M pro represents a key target for the inhibition of viral replication specifically for SARS-CoV-2. We have used a virtual screening strategy by targeting M pro against a library of commercially available compounds to identify potential inhibitors. After initial identification of hits by molecular docking-based virtual screening further MM/GBSA, predictive ADME analysis, and molecular dynamics simulation were performed. The virtual screening resulted in the identification of twenty-five top scoring structurally diverse hits that have free energy of binding (ΔG) values in the range of -26-06 (for compound AO-854/10413043) to -59.81 Kcal/mol (for compound 329/06315047). Moreover, the top-scoring hits have favorable AMDE properties as calculated using in silico algorithms. Additionally, the molecular dynamics simulation revealed the stable nature of protein-ligand interaction and provided information about the amino acid residues involved in binding. Overall, this study led to the identification of potential SARS-CoV-2 M pro hit compounds with favorable pharmacokinetic properties. We believe that the outcome of this study can help to develop novel M pro inhibitors to tackle this pandemic.Communicated by Ramaswamy H. Sarma.

To address coronavirus disease (COVID-19), currently, no effective drug or vaccine is available. In this regard, molecular modeling approaches are highly useful to discover potential inhibitors of the main protease (M pro ) enzyme of SARS-CoV-2. Since, the M pro enzyme plays key roles in mediating viral replication and transcription; therefore, it is considered as an attractive drug target to control SARS-CoV-2 infection. By using structure-based drug design, pharmacophore modeling, and virtual high throughput drug screening combined with docking and all-atom molecular dynamics simulation approach, we have identified five potential inhibitors of SARS-CoV-2 M pro . MD simulation studies revealed that compound 54035018 binds to the M pro with high affinity (Δ G bind -37.40 kcal/mol), and the complex is more stable in comparison with other protein-ligand complexes. We have identified promising leads to fight COVID-19 infection as these compounds fulfill all drug-likeness properties. However, experimental and clinical validations are required for COVID-19 therapy.Communicated by Ramaswamy H. Sarma.

The outbreak of coronavirus disease 2019 (COVID-19) at the end of 2019 affected global health. Its infection agent was called severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Wearing a mask, maintaining social distance, and vaccination are effective ways to prevent infection of SARS-CoV-2, but none of them help infected people. Targeting the enzymes of SARS-CoV-2 is an effective way to stop the replication of the virus in infected people and treat COVID-19 patients. SARS-CoV-2 main protease is a therapeutic target which the inhibition of its enzymatic activity prevents from the replication of SARS-CoV-2. A large database of molecules has been searched to identify new inhibitors for SARS-CoV-2 main protease enzyme. At the first step, ligand screening based on similarity search was used to select similar compounds to known SARS-CoV-2 main protease inhibitors. Then molecules with better predicted pharmacokinetic properties were selected. Structure-based virtual screening based on the application of molecular docking and molecular dynamics simulation methods was used to select more effective inhibitors among selected molecules in previous step. Finally two compounds were considered as SARS-CoV-2 main protease inhibitors.

Different esters were found potential against microorganisms, and could be a better choice to solve the multidrug resistant (MDR) pathogenic global issue due to their improved biological and pharmacokinetic properties. In this view, several 4- t -butylbenzoyl uridine esters 4-15 with different aliphatic and aromatic groups were synthesized for antimicrobial, physicochemical and biological studies. In vitro antimicrobial tests against nine bacteria and three fungi along with prediction of activity spectra for substances (PASS) indicated promising antifungal functionality of these uridine esters compared to the antibacterial activities. In support of this observation their cytotoxicity and molecular docking studies have been performed against lanosterol 14α-demethylase (CYP51A1) and Aspergillus flavus (1R51). Significant binding affinities were observed against SARS-CoV-2 main protease (7BQY) considering hydroxychloroquine (HCQ) as standard. ADMET predictions were investigated to evaluate their absorption, metabolism and toxic properties. Most of the uridine esters showed better results than that of the HCQ. Overall, the present study might be useful for the development of uridine-based novel MDR antimicrobial and COVID-19 drugs.