Integrated computational approach towards repurposing of antimalarial drug against SARS-CoV-2 main protease.

Huge vaccination drives are underway around the world for the ongoing COVID-19 pandemic. However, the search for antiviral drugs is equally crucial. As new drug discovery is a time-consuming process, repurposing of existing drugs or developing drug candidates against SARS-CoV-2 will make the process faster. Considering this, 63 approved and developing antimalarial compounds were selected to screen against main protease (Mpro) and papain-like protease (PLpro) of SARS-CoV-2 using in silico methods to find out possible new drug candidate(s). Out of 63 compounds, epoxomicin showed the best binding affinity against the Mpro with CDocker energy of - 57.511 kcal/mol without any toxic effect. This compound was further taken for molecular dynamic simulation study, where the Mpro-epoxomicin complex was found to be stable with binding free energy - 79.315 kcal/mol. The possible inhibitory potential of the selected compound was determined by 3D-QSAR analysis and found to be 0.4447 µM against SARS-CoV-2 Mpro. Finally, the structure activity relationship of the compound was analyzed and two fragments responsible for overall good binding affinity of the compound at the active site of Mpro were identified. This study suggests a safe antimalarial drug, namely epoxomicin, as a probable inhibitor of SARS-CoV-2 Mpro which needs further validation by in vitro/in vivo studies before clinical use. Supplementary Information: The online version contains supplementary material available at 10.1007/s11224-022-01916-0.

Repurposing of phytomedicine-derived bioactive compounds with promising anti-SARS-CoV-2 potential: Molecular docking, MD simulation and drug-likeness/ADMET studies.

In view of the potential of traditional plant-based remedies (or phytomedicines) in the management of COVID-19, the present investigation was aimed at finding novel anti-SARS-CoV-2 molecules by in silico screening of bioactive phytochemicals (database) using computational methods and drug repurposing approach. A total of 160 compounds belonging to various phytochemical classes (flavonoids, limonoids, saponins, triterpenoids, steroids etc.) were selected (as initial hits) and screened against three specific therapeutic targets (Mpro/3CLpro, PLpro and RdRp) of SARS-CoV-2 by docking, molecular dynamics simulation and drug-likeness/ADMET studies. From our studies, six phytochemicals were identified as notable ant-SARS-CoV-2 agents (best hit molecules) with promising inhibitory effects effective against protease (Mpro and PLpro) and polymerase (RdRp) enzymes. These compounds are namely, ginsenoside Rg2, saikosaponin A, somniferine, betulinic acid, soyasapogenol C and azadirachtin A. On the basis of binding modes and dynamics studies of protein-ligand intercations, ginsenoside Rg2, saikosaponin A, somniferine were found to be the most potent (in silico) inhibitors potentially active against Mpro, PLpro and RdRp, respectively. The present investigation can be directed towards further experimental studies in order to confirm the anti-SARS-CoV-2 efficacy along with toxicities of identified phytomolecules.

Computational guided identification of potential leads from Acacia pennata (L.) Willd. as inhibitors for cellular entry and viral replication of SARS-CoV-2.

BACKGROUND: Coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) started in 2019 and is still an on-going pandemic. SARS-CoV-2 uses a human protease called furin to aid in cellular entry and its main protease (Mpro) to achieve viral replication. By targeting these proteins, scientists are trying to identify phytoconstituents of medicinal plants as potential therapeutics for COVID-19. Therefore, our study was aimed to identify promising leads as potential inhibitors of SARS-CoV-2 Mpro and furin using the phytocompounds reported to be isolated from Acacia pennata (L.) Willd. RESULTS: A total of 29 phytocompounds were reported to be isolated from A. pennata. Molecular docking simulation studies revealed 9 phytocompounds as having the top 5 binding affinities towards SARS-CoV-2 Mpro and furin. Among these phytocompounds, quercetin-3-O-α-L-rhamnopyranoside (C_18), kaempferol 3-O-α-L-rhamnopyranosyl-(1 → 4)-ß-D-glucopyranoside (C_4), and isovitexin (C_5) have the highest drug score. However, C_18 and C_4 were not selected for further studies due to bioavailability issues and low synthetic accessibility. Based on binding affinity, molecular properties, drug-likeness, toxicity parameters, ligand interactions, bioavailability, synthetic accessibility, structure-activity relationship, and comparative analysis of our experimental findings with other studies, C_5 was identified as the most promising phytocompound. C_5 interacted with the active site residues of SARS-CoV-2 Mpro (GLU166, ARG188, GLN189) and furin (ASN295, ARG298, HIS364, THR365). Many phytocompounds that interacted with these amino acid residues were reported by other studies as potential inhibitors of SARS-CoV-2 Mpro and furin. The oxygen atom at position 18, the -OH group at position 19, and the 6-C-glucoside were identified as the pharmacophores in isovitexin (also known as apigenin-6-C-glucoside). Other in-silico studies reported apigenin as a potential inhibitor of SARS-CoV-2 Mpro and apigenin-o-7-glucuronide was reported to show stable conformation during MD simulations with SARS-CoV-2 Mpro. CONCLUSION: The present study found isovitexin as the most promising phytocompound to potentially inhibit the cellular entry and viral replication of SARS-CoV-2. We also conclude that compounds having oxygen atom at position 18 (C-ring), -OH group at position 19 (A-ring), and 6-C-glucoside attached to the A-ring at position 3 on a C6-C3-C6 flavonoid scaffold could offer the best alternative to develop new leads against SARS-CoV-2.

Identification of potential plant-based inhibitor against viral proteases of SARS-CoV-2 through molecular docking, MM-PBSA binding energy calculations and molecular dynamics simulation.

The Coronavirus disease 2019 (COVID-19), caused by the novel coronavirus, SARS-CoV-2, has recently emerged as a pandemic. Here, an attempt has been made through in-silico high throughput screening to explore the antiviral compounds from traditionally used plants for antiviral treatments in India namely, Tea, Neem and Turmeric, as potential inhibitors of two widely studied viral proteases, main protease (Mpro) and papain-like protease (PLpro) of the SARS-CoV-2. Molecular docking study using BIOVIA Discovery Studio 2018 revealed, (-)-epicatechin-3-O-gallate (ECG), a tea polyphenol has a binding affinity toward both the selected receptors, with the lowest CDocker energy - 46.22 kcal mol-1 for SARS-CoV-2 Mpro and CDocker energy - 44.72 kcal mol-1 for SARS-CoV-2 PLpro, respectively. The SARS-CoV-2 Mpro complexed with (-)-epicatechin-3-O-gallate, which had shown the best binding affinity was subjected to molecular dynamics simulations to validate its binding affinity, during which, the root-mean-square-deviation values of SARS-CoV-2 Mpro-Co-crystal ligand (N3) and SARS-CoV-2 Mpro- (-)-epicatechin-3-O-gallate systems were found to be more stable than SARS-CoV-2 Mpro system. Further, (-)-epicatechin-3-O-gallate was subjected to QSAR analysis which predicted IC50 of 0.3281 nM against SARS-CoV-2 Mpro. Overall, (-)-epicatechin-3-O-gallate showed a potential binding affinity with SARS-CoV-2 Mpro and could be proposed as a potential natural compound for COVID-19 treatment.

Computational guided identification of a citrus flavonoid as potential inhibitor of SARS-CoV-2 main protease.

Although vaccine development is being undertaken at a breakneck speed, there is currently no effective antiviral drug for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causing COVID-19. Therefore, the present study aims to explore the possibilities offered by naturally available and abundant flavonoid compounds, as a prospective antiviral drug to combat the virus. A library of 44 citrus flavonoids was screened against the highly conserved Main Protease (Mpro) of SARS-CoV-2 using molecular docking. The compounds which showed better CDocker energy than the co-crystal inhibitor of Mpro were further revalidated by flexible docking within the active site; followed by assessment of drug likeness and toxicity parameters. The non-toxic compounds were further subjected to molecular dynamics simulation and predicted activity (IC50) using 3D-QSAR analysis. Subsequently, hydrogen bonds and dehydration analysis of the best compound were performed to assess the binding affinity to Mpro. It was observed that out of the 44 citrus flavonoids, five compounds showed lower binding energy with Mpro than the co-crystal ligand. Moreover, these compounds also formed H-bonds with two important catalytic residues His41 and Cys145 of the active sites of Mpro. Three compounds which passed the drug likeness filter showed stable conformation during MD simulations. Among these, the lowest predicted IC50 value was observed for Taxifolin. Therefore, this study suggests that Taxifolin, could be a potential inhibitor against SARS-CoV-2 main protease and can be further analysed by in vitro and in vivo experiments for management of the ongoing pandemic.

Potential anti-viral activity of approved repurposed drug against main protease of SARS-CoV-2: an in silico based approach.

The Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) which was first reported in Wuhan province of China, has become a deadly pandemic causing alarmingly high morbidity and mortality. In the absence of new targeted drugs and vaccines against SARS-CoV-2 at present, the choices for effective treatments are limited. Therefore, considering the exigency of the situation, we focused on identifying the available approved drugs as potential inhibitor against the promising Coronavirus drug target, the Main Protease, using computer-aided methods. We created a library of U. S. Food and Drug Administration approved anti-microbial drugs and virtually screened it against the available crystal structures of Main Protease of the virus. The study revealed that Viomycin showed the highest -CDocker energy after docking at the active site of SARS-CoV-2 Main Protease. It is noteworthy that Viomycin showed higher -CDocker energy as compared to the drugs currently under clinical trial for SARS-CoV-2 treatment viz. Ritonavir and Lopinavir. Additionally, Viomycin formed higher number of H-bonds with SARS-CoV-2 Main Protease than its co-crystallised inhibitor compound N3. Molecular dynamics simulation further showed that Viomycin embedded deeply inside the binding pocket and formed robust binding with SARS-CoV-2 Main Protease. Therefore, we propose that Viomycin may act as a potential inhibitor of the Main Protease of SARS-CoV-2. Further optimisations with the drug may support the much-needed rapid response to mitigate the pandemic.Communicated by Ramaswamy H. Sarma.