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SARS-CoV-2, the new coronavirus variant, has been a worldwide health crisis that may outbreak at any time in the future. Over spans of human history, preparations derived from natural products have always been recognized as a preliminary source of medications. Taking into account the SARS-CoV-2 main protease (Mpro) as the essential element of the viral cycle and as a main target, herein we highlight a computer-aided comprehensive virtual screening for a focused chemical list of 14 laulimalides marine macrolides against SARS-CoV-2 Mpro using a set of integrated modern computational techniques including molecular docking (MDock), molecule dynamic simulations (MDS) and structure–activity relationships (SARs). Based on their remarkable ligand-protein energy scores and relevant binding affinities with SARS-CoV-2 (Mpro) pocket residues, two promising macrolides [laulimalides LA4 (6) and LA18 (13)] are selected as proposed inhibitor compounds. Consequently, they are thermodynamically investigated by deciphering their MD simulations at 100 ns, where they show noticeable stability within the accommodated (Mpro) pockets. Moreover, in-depth SARs studies suggest crucial roles for C-23 substituted side chain and C-20 methoxy as essential pharmacophoric structural features for activity. Further in vitro/vivo examinations of the selected marine macrolides would pave the way towards developing effective antiviral drugs from natural resources.

Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) causes COVID-19, a disease currently spreading around the world. Some drugs are underway or being used to combat this disease. Several proteins of the virus can be targeted in therapeutic approaches. Two structural proteins, membrane (M), envelope (E) have critical roles in virus life cycle, such as assembly, budding, envelope formation and pathogenesis. Here, we employed the in silico strategies to identify and evaluate the selected potential compounds against M and E proteins. For this, the structures of proteins were modeled and then several groups of compounds as FDA approved, natural products or under clinical trials were screened from DrugBank and ZINC databases. The selected dockings were analyzed and the ligands with best binding affinity scores were subjected to evaluate drug-likeness and medicinal chemistry friendliness through prediction of ADMET properties. Normal mode analyses were also performed for six selected complexes to explore the collective motions of proteins. Molecular dynamic (MD) simulation was also performed to calculate the stability of two docked protein–ligand complexes. The results revealed that several compounds had high affinity to the proteins along with some acceptable profiles of mobility and deformability, especially, for M protein.

COVID-19 is the last disease caused by SARS-CoV-2 associated with a severe immune response and lung damage. The main protease (M^pro) has a vital role in SARS-CoV-2 proliferation. Moreover, humans lack homologous M^pro, which makes the M^pro a suitable drug target for the development of SARS-CoV-2 drugs. The purchasable L5000 library (Selleckchem Inc) includes 99,040 compounds that were used for virtual screening. After molecular docking and ADME studies, we selected a compound (WAY-604395) with a potent binding affinity to the M^pro active site and acceptable ADME properties compared to the reference drug (nelfinavir). Molecular dynamics (MD) simulation outcomes have proved that the M^pro-WAY604395 complex possesses a considerable value of flexibility, stability, compactness and binding energy. Our Molecular Mechanics Poisson–Boltzmann Surface Area (MM-PBSA) calculation demonstrates that WAY-604395 is more potent ($-$272.19kcal mol${}^{-1}$) in comparison with nelfinavir ($-$173.39kcalmol${}^{-1}$) against SARS-CoV-2 M^pro. In conclusion, we suggest that WAY-604395 has the potential for the treatment of SARS-CoV-2 by inhibition of the M^pro.

SARS-CoV-2 entrance to the host cells is started by the interaction between receptor binding domain (RBD) of the spike (S) protein on the virus with the angiotensin-converting enzyme 2 (ACE2) receptor which is very important in the onset of viral infection. Interference with this interaction can be a promising way to prevent Covid-19 infection. In this study, a novel potential therapeutic peptide was designed in silico based on the key interacting amino acids of ACE2 against SARS-CoV-2 S protein. In our computational analysis, a peptide consisting of residues 19–48 of ACE2 was chosen as the wild-type peptide. Based on this peptide, six mutant peptides (Mu_P1-6) were designed and then assessed in term of interaction with S protein. The result of protein-peptide docking by HADDOCK web server and then immunological analysis by SVMTriP epitope prediction tool leads to choose Mu_P3 as the best mutant. Molecular dynamics simulations of wild-type peptide-S protein complex and Mu_P3-S protein complex, showed Mu_P3 has better interaction with S protein than wild type peptide (interaction energies $-897.14$ vs. $-784.13$ (kJ/mol)) which can be a potential therapeutic peptide for Covid-19 pandemic.

It has been a great challenge for scientists to develop an anti-Covid drug/vaccine with fewer side effects, since the coronavirus pandemic began. Of course, the prescription of chiral drugs (chloroquine or hydroxychloroquine) has been proved wrong because these chiral drugs neither kill the virus nor eliminate it from the body, but block SARS-CoV-2 from binding to human cells. Another hurdle facing the world is not only the positive test of the patient recovered from coronavirus, but also the second wave of Covid-19. Hence, the world demands such a drug or drug combination which not only prevents the entry of SARS-CoV-2 in the human cell but also ejects it or its material from the body completely. The current computational study not only utilizes a structure-based drug design approach to find possible drug candidates but also explains (i) why the prescription of chiral drugs was not satisfactory, (ii) what types of modification can make their prescription satisfactory, (iii) the mechanism of action of chiral drugs (chloroquine and hydroxychloroquine) to block SARS-CoV-2 from binding to human cells, and (iv) the strength of mefloquine to eliminate SARS-CoV-2. As the main protease (M${}^{pro}$) of microbes is considered as an effective target for drug design and development, the binding affinities of mefloquine with the M${}^{pro}$ of JC virus and SARS-CoV-2 were calculated, and then compared to know the eliminating strength of mefloquine against SARS-CoV-2. The M${}^{pro}$ of JC virus was taken because mefloquine has already shown a tremendous result of eliminating it from the body. The prescription of a combination of S-$(+)$-hydroxychloroquine and $(+)$-mefloquine is considered as a boon by the predicted study.

Severe acute respiratory syndrome coronavirus (SARS-CoV)-2, a novel coronavirus, is a member of the Coronoviridae family that has spread worldwide. Developing efficacious therapeutics for the treatment of SARS-CoV-2 is of high priority. Therefore, in this study, the chemical constituents obtained from Tinospora cordifolia are investigated for their in-silico interaction with protein targets crucial for SARSCoV-2 infection and cytokine storm. The five important targets chosen for SARSCoV-2 were the main protease (Mpro), Spike receptor binding domain (Spike-RBD), RNA-dependent RNA polymerase (RdRp or Nsp12), nonstructural protein 15 (Nsp15) of SARS-CoV-2 and the host angiotensin converting enzyme-2 (ACE-2) spike-RBD binding domain and cytokine receptors TNF-$\alpha$ (Tumor Necrosis Factor-$\alpha$) and IL-6 (Interleukine-6). This was accomplished using Maestro 12.4 (Schrodinger Suite) to obtain docking scores. Also, the absorption, distribution, metabolism, elimination, and toxicity parameters (ADMET) were determined using Maestro QikProp modules. The results of computational study revealed that four constituents Cordifolioside-A, Palmatoside-E, Tinocordioside and Tinosporaside significantly antagonize the five targets of SARS-CoV-2 by binding in the binding pocket with docking score ranging from −9.664 to −6.488 kcal/mol and shows drug-like property and also effectively inhibit cytokine storm by antagonizing the TNF-$\alpha$ and IL-6 receptors. Promising drug-like properties, excellent docking scores, and binding pose against each target makes the screened compounds as possible lead candidate which can be further evaluated in future studies to assess their in vitro and in vivo efficacy against SARS-CoV-2. The structure of these compounds can be used further for optimization and design of drugs against COVID-19.

SARS-CoV-2 is an endemic positive-sense RNA virus naturally transmissible between numerous species with notable infectivity and associated mortality. It is characterized by a poly-adenylated structure capping the genomic terminus. This poly(A) tail is crucial to a cascade of viral replicative activity occurring both extra- and intra-cellular during infection. As a route to proposing potential chemotherapy, this study suggests simple biplanar adenine quadruplexes (A4s) which may fold in specific sequences of the viral genome. To the best of our knowledge, uniquely biplanar A4s have not been previously described in any context. Using molecular modeling techniques and molecular dynamics simulations, some of these non-canonical structures show reasonable stability in a biological context. Notably, mRNA configured as a biplanar A4, shows less dynamic activity than DNA equivalents. This observation may be especially relevant in a physiological context. Furthermore, in contrast to well-characterized guanine quadruplexes, co-ordination with cations appears not to impact on stability. Our molecular dynamics simulations and analyses demonstrate that some A4s are stable in biologically relevant terms. These conclusions may apply to SARS-CoV-2, its variants and other pathogenic RNA viruses.

Coronaviruses are a large family of viruses that can cause respiratory infections with varying severity from common cold to severe diseases such as novel coronavirus disease (COVID-19). COVID-19 has been declared as a global pandemic by the World Health Organization on March 11, 2020 and with the development of vaccines it slowed down as of this date. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) uses its spike glycoprotein (Sgp) to bind human angiotensin-converting enzyme 2 (hACE2) receptor, and mediates membrane fusion and virus entry. The recognition of Sgp to human ACE2 and its high affinity for it has been of great importance since this provides the first step in viral entry to human cells. Therefore, it is crucial to identify key residues (hotspots) in this process. In this study, computational alanine scanning has been performed for Sgp and hACE2. The residues identified with significance in binding and other residues in close proximity were studied further through molecular mechanics-based protein binding free energy change prediction methods. Moreover, the interfacial residues in both proteins were investigated for their cooperative binding. Additionally, folding free energy changes upon mutation to Ala were calculated to assess their effect on stability of Sgp and hACE2. Our results taken together with findings from previous studies revealed the residues that are most significant and are relatively significant in binding of Sgp to human ACE2 protein.

The ongoing eruption of the COVID-19 pandemic instigated by severe-acute-respiratory-syndrome-coronavirus 2 (SARS-CoV-2) has produce enormous damage to the world. The need of the hour is to stop this pandemic by inhibiting the main protease (M^Pro) of SARS-CoV-2, which is primarily involved in viral replication. Our study aims to find potential inhibitors for M^Pro by docking marine fungi-based 90 antiviral compounds against SARS-CoV-2. Among these, 11 antiviral compounds (obeying Lipinski RO5) are selected from 90 docked antiviral compounds on the basis of binding energy range ($-$6.4kcal/mol to $-$9kcal/mol) and low inhibition constant values (0.23$\mu$M to 2.5$\mu$M) as compared with remdesivir (reference compound) toward M^Pro of SARS-CoV-2. Tryptoquivaline F, arisugacin B, and arisugacin A antiviral compounds exhibited effective hydrogen and hydrophobic (alkyl, $\pi$-alkyl, and $\pi$-anion) interactions and are expected to be potential protease inhibitors. Drug-likeness of these lead compounds are elaborated by boiled-egg and bioavailability radar map. The toxicity profile showed that the lead compounds L1, L2, and L3 have no AMES toxicity, skin sensitization, and cardiac toxicity. The RMSD graph proposed that all the complexes, i.e. L1, L2, and L3 are in the adequate RMSD range with the average value of 2.1Å. All the complex systems of L1, L2, and L3 showed fluctuations in the acceptable RMSF range of 1.5Å to 3Å. The molecular dynamics simulation proved the stability of docked complexes L1, L2, and L3 in the binding pocket of main protease. The average hydrogen count of all complexes is $\mathrm{\text{L1}}=69.5$, $\mathrm{\text{L2}}=67.7$, and $\mathrm{\text{L3}}=68.6$ H-bonds. The complexes L1-M^Pro, L2-M^Pro, and L3-M^Pro have an average value of $R_g$ as 22.44Å, 22.63Å, and 22.50Å, respectively. The lead compounds L1 (tryptoquivaline F), L2 (arisugacin b), and l3 (arisugacin A) in this study are the most promising inhibitors of SARS-CoV-2 main protease M^Pro, which are not reported in ealier studies. Our findings will evoke the scientific interest for their further in vitro and in vivo experimental studies.

SARS-CoV-2, which causes COVID-19 disease, has proven to be a disastrous pandemic due to its contagious nature. This study has been planned to theoretically explore some antidotes against this virus from natural compounds. A total of 150 compounds from the shogaol class and shogaol derivatives (SDs) have been screened whereas 50 among those, which obeyed Lipinski’s Rule of Five (Ro5), have further been investigated using molecular docking techniques. Furthermore, reference antiviral drug chloroquine (ChQ) and Co-Crystallized inhibitor have also been studied against M^pro of SARS-CoV-2 for comparing the potential of our docked ligands. Surprisingly, 78% of our docked ligands have shown binding energies and inhibition constants lower than ChQ and all ligands showed these values lower than an inhibitor. We further visualized the nature of intermolecular interactions for the best docked six ligands, which have shown higher binding affinities. We have also assessed ADMET properties for three ligands that displayed visually the best intermolecular interactions. Quantum analysis of three selected ligands L4, L5, and L9 has proved their reactivity and kinetic stability. Moreover, molecular dynamic simulations over 60ns have been run for free M^pro and its selected three ligand-protein complexes for evaluating conformational stability and residual flexibility of docked complexes. Furthermore, 100ns the MD simulations have been performed for two ligand complexes L4, L5 (with negative binding free energy), and inhibitor. Available parameters suggest stable complexes for our ligands and could be active drugs against SARS-CoV-2 in near future.

Angiotension-converting enzyme 2 (ACE2) is the host receptor of the serious-acute respiratory syndrome coronavirus 2 (Sars-CoV-2) spike protein. In this article, the interaction of ACE2 with the receptor binding domains (RBD) of Wuhan-Hu-1 and United Kingdom (UK) and South African (SA) variants is examined in silico. Their Gibbs free energies were computed using a protein binding energies prediction model. The interaction characteristics of RBDs with possible inhibitory compounds as well as a standard drug, Paxlovid, were also investigated, and Gibbs free energies were computed. Molecular modeling, molecular dynamics and molecular docking methods were employed and the results are compared and discussed.

The global spread of COVID-19 caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) originated in Wuhan in December 2019, created a massive health crisis, and disrupted the world economy. Much research has been conducted to discover drugs, develop vaccines, and find repurposable drugs against the disease. Computational drug repurposing, the process of determining new uses for approved drugs through computational techniques, becomes an effective solution to fight the COVID-19 pandemic. This study aims to investigate and prioritize potential drugs against SARS-CoV-2 through an integrated network-based approach. We propose an ensemble approach based on network inference and inductive matrix completion (NIMCVDA) for virus–drug association prediction to identify antivirals against COVID-19. We constructed a heterogeneous drug–virus network using intra-similarities of virus genomic sequences and drug chemical structures and existing associations between viruses and drugs. A network inference method is used to infer missing drug–virus edges. Based on this, existing drug–virus association matrix is reconstructed. Finally, more accurate association scores between drugs and viruses are computed using the inductive matrix completion algorithm. The proposed method achieved an AUC of 0.9020 on five-fold cross-validation and 0.8786 on leave-one-out cross-validation. We compared the performance of the model with related approaches. In addition, we carried out case studies on the top-predicted drugs and implemented our model with other datasets to verify prediction performance. Our work prioritized repurposable drugs to battle with COVID-19 epidemic. The cross-validation results and case studies illustrate that the top-predicted drugs are strong candidates for further biological tests.

SARS-CoV-2 Main protease (M^pro) is pivotal in viral replication and transcription. M^pro mediates proteolysis of translated products of replicase genes ORF1a and ORF1ab. Surveying pre-clinical trial M^pro inhibitors suggests potential enhanced efficacy for some moieties. Concordant with promising in vitro and in silico data, the protease inhibitor GC376 was chosen as a lead. Modification of GC376 analogues yielded a series of promising M^pro inhibitors. Design optimization identified compound G59i as lead candidate, displaying a binding energy of $-$10.54 kcal/mol for the complex. Robust interactivity was noted between G59i and M^pro. With commendable ADMET characteristics and enhanced potency, further G59i analysis may be advantageous; moreover, identified key M^pro residues could contribute to the design of neotenic inhibitors.

The novel coronavirus disease 19 (COVID-19) has resulted in an estimated 20 million excess deaths and the recent resurgence of COVID-19 in China is predicted to result in up to 1 million deaths over the next few months. With vaccines being ineffective in the case of immunocompromised patients, it is important to continue our quest for safe, effective and affordable drugs that will be available to all countries. Drug repurposing is one of the strategies being explored in this context. Recently, out of the 7817 drugs approved worldwide, 214 candidates were systematically down-selected using a combination of 11 filters including FDA/TGA approval status, assay data against SARS-CoV-2, pharmacokinetic, pharmacodynamic and toxicity profiles. These down-selected drugs were subjected in this study to virtual screening against various SARS-CoV-2 targets followed by molecular dynamics studies of the best scoring ligands against each target. The chosen molecular targets were spike receptor binding domain, nucleocapsid protein RNA binding domain and key nonstructural proteins 3, 5 and 12–14. Four drugs approved for other indications — alendronate, cromolyn, natamycin and treprostinil — look sufficiently promising from our in-silico studies to warrant further in-vitro and in-vivo investigations as appropriate to ascertain their extent of antiviral activities.

The primary aim of this investigation is to shed light on potential targets within the main protease Mpro, spike protein of SARS-CoV-2, and Angiotensine converting enzyme 2 (ACE2) for the exploration of novel inhibitors derived from therapeutic natural compounds originating from Atriplex halimus (AH). Many constituents were discerned within AH extracts through comprehensive gas chromatography/mass spectrometry (GC/MS). Notably, compounds, such as oleocanthal and methyl stearate, exhibited promising attributes across various biological activities, including inhibition of key proteins associated with SARS-CoV-2. Furthermore, absorption, distribution, metabolism, excretion, and toxicity (ADMET) settings were evaluated to explore the potential safety and viability of these compounds for pharmaceutical application, affirming their non-interference with human physiology and thus suggesting their suitability for pharmaceutical use. Catechin, epigallocatechin, and methyl stearate were discovered to be the compounds with the highest affinity to the studied protein showing a great potential to be inhibitors to COVID-19. Consequently, this discovery highlights Atriplex halimus as a promising candidate for utilization in combating the virus.