ABSTRACT
Background: Due to the complexities of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), an effective medicinal treatment protocol for this lethal disease with a high prevalence has not been approved yet. This study aimed to explore the efficacy of the main alkaloids of Isatis indigotica, one of the richest plant sources of alkaloids against SARS-CoV-2 targets computationally. Materials and Methods: 3D structures of the target proteins including 3CLpro;PLpro, and RdRp were downloaded from Protein Data Bank. The structures of ligands were retrieved from PubChem database or optimized by ORCA program. Ritonavir, Lopinavir, Sofosbuvir, and Remdesivir were selected as control inhibitors. Docking calculations were performed by AutoDock Vina option and top-ranked compounds were subjected to molecular dynamics simulation by Gromacs 5.1.4 simulation package. Result: The results showed that all 15 compounds had stronger interactions with PLpro in comparison to the other enzymes. Dihydroxylisopropylidenylisatisine A binds to the active site of PLpro with highest affinity (-9.3 kcal/mol) which is even more than the binding constants of Ritonavir and Lopinavir. Of the 15 compounds, Dihydroxylisopropylidenylisatisine A and Isatibisindosulfonic acid B had the highest tendency to bind to 3CLpro. Dihydroxylisopropylidenylisatisine A, Indirubin, Insatindibisindolamide A, Indigo, Insatindibisindolamide B, Isatibisindosulfonic acid B and Isatindosulfonic acid B had the highest RdRp binding affinity even more Remdesivir. Conclusion: Based on the results, the highest and weakest interaction with all three enzymes was observed for Dihydroxylisopropylidenylisatisine A and Epigoitrin, respectively. Based on these findings, Dihydroxylisopropylidenylsatistine A might be potential therapeutic candidate against SARS-CoV-2.
ABSTRACT
Across 218 countries, since March 2020, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection has been a reason for concern. Doctors as well as researchers. stand together to find a treatment for this pandemic. The virus attaches to the host cells via transmembrane spike glycoprotein. The glycoprotein has affinity for human angiotensin-converting enzyme 2 and is dimeric. Thus, the virus attaches to the ACE receptors through the receptor-binding domain (SARS-CoV-2 RBD Spro). Further, the main protease (Mpro), a chymotrypsin-like protease (3CLpro), plays a critical role in post-translational modifications, thereby affecting viral survival. Thus, targeting these viral markers can not only block the fusion with host cells, but also affect replication of the virus. Ancient civilizations have been using plants, herbs as well as spices for their medicinal values as antiviral, antiinflammatory, antipyretic, antimicrobial and many more. The rich array of phytochemicals in these spices endows them with these beneficial properties, and hence they are largely being looked as agents for therapeutic use. However, the journey from laboratory for drug development is a time-consuming process as it starts from trying to identify the major therapeutic component to its pre-clinical studies, clinical and then its marketing as a drug. In the current pandemic where loss of human life has been in millions, a faster and more efficient modality like in silico studies can help escalate this search for a therapy thereby saving mankind. This study is a comprehensive review on results of in silico approaches conducted in near future in an attempt to evolve an ideal therapeutic candidate for ending the pandemic. Results of research conducted on phytochemicals from medicinal and aromatic plants as potential therapeutic candidates using tools of bioinformatics and computational modelling are hereby discussed.
ABSTRACT
Various protein/receptor targets have been discovered through in-silico research. They are expanding rapidly due to their extensive advantage of delivering new drug candidates more quickly, efficiently, and at a lower cost. The automation of organic synthesis and biochemical screening will lead to a revolution in the entire research arena in drug discovery. In this research article, a few fungal metabolites were examined through an in-silico approach which involves major steps such as (a) Molecular Docking Analysis, (b) Drug likeness and ADMET studies, and (c) Molecular Dynamics Simulation. Fungal metabolites were taken from Antibiotic Database which showed antiviral effects on severe viral diseases such as HIV. Docking, Lipinski's, and ADMET analyses investigated the binding affinity and toxicity of five metabolites: Chromophilone I, iso; F13459; Stachyflin, acetyl; A-108836; Integracide A (A-108835). Chromophilone I, iso was subjected to additional analysis, including a 50 ns MD simulation of the protein to assess the occurring alterations. This molecule's docking data shows that it had the highest binding affinity. ADMET research revealed that the ligand might be employed as an oral medication. MD simulation revealed that the ligand-protein interaction was stable. Finally, this ligand can be exploited to develop SARS-CoV-2 therapeutic options. Fungal metabolites that have been studied could be a potential source for future lead candidates. Further study of these molecules may result in creating an antiviral drug to battle the SARS-CoV-2 virus.
ABSTRACT
Purpose: A novel coronavirus (COVID-19) that has not been previously identified in humans and has no specific treatment has recently spread. Treatment trials using antiviral and immune-modulating drugs such as hydroxychloroquine (HCQ) were used to control this viral outbreak however several side effects have emerged. Berberine (BER) is an alkaloid that has been reported to reveal some pharmacological properties including antioxidant and antimicrobial activities. Additionally, Zinc oxide nanoparticles (ZnO-NPs) possess potent antioxidant and anti-inflammatory properties. Therefore, this study was undertaken to estimate the efficiency of both BER and synthetic ZnO/BER complex as an anti-COVID-19 therapy. Methods: First, the ZnO/BER complex was prepared by the facile mixing method. Then in vitro studies on the two compounds were conducted including VeroE6 toxicity, anti-COVID-19 activity, determination of inhibitory activity towards papain-like proteinase (PL pro) and spike protein- and receptor- binding domain (RBD) as well as assessment of drug toxicity on RBCs. Results: The results showed that ZnO/BER complex acts as an anti-COVID-19 by inhibiting spike protein binding with angiotensin-converting enzyme II (ACE II), PL pro activity, spike protein and E protein levels, and expression of both E-gene and RNA dependent RNA polymerase (RdRp) at a concentration lower than that of BER or ZnO-NPs alone. Furthermore, ZnO/BER complex had antioxidant and antimicrobial properties where it prevents the auto oxidation of 2,2-Diphenyl-1-picrylhydrazyl (DPPH) and the culture of lower respiratory system bacteria that affected Covid 19 patients. The ZnO/BER complex prevented as well the HCQ cytotoxic effect on both RBC and WBC (in vitro) and hepatotoxicity, nephrotoxicity and anemia that occurred after HCQ long administration in vivo. Conclusion: The ZnO/BER complex can be accounted as promising anti-COVID 19 candidate because it inhibited the virus entry, replication, and assembly. Furthermore, it could be used to treat a second bacterial infection that took place in hospitalized COVID 19 patients. Moreover, ZnO/BER complex was found to eliminate the toxicity of long-term administration of HCQ in vivo.
ABSTRACT
The emerging paradigm shift from 'one molecule, one target, for one disease' towards 'multi-targeted small molecules' has paved an ingenious pathway in drug discovery in recent years. We extracted this idea for the investigation of drugs for COVID-19. Perceiving the importance of organosulfur compounds, seventy-six known organosulfur compounds were screened and studied for the interaction with multiple SARS-CoV-2 target proteins by molecular dynamics simulation. Lurasidone and its derivatives displayed substantial binding affinity against five proteins (Mpro, PLpro, Spro, helicase and RdRp). The pharmacokinetics, ADMET properties and target prediction studies performed in this work further potentiates the effectiveness against SARS-CoV-2.
ABSTRACT
The pandemic caused by novel coronavirus disease 2019 (COVID-19) infecting millions of populations worldwide and counting, has demanded quick and potential therapeutic strategies. Current approved drugs or molecules under clinical trials can be a good pool for repurposing through in-silico techniques to quickly identify promising drug candidates. The structural information of recently released crystal structures of main protease (Mpro) in APO and complex with inhibitors, N3, and 13b molecules was utilized to explore the binding site architecture through Molecular dynamics (MD) simulations. The stable state of Mpro was used to conduct extensive virtual screening of the aforementioned drug pool. Considering the recent success of HIV protease molecules, we also used anti-protease molecules for drug repurposing purposes. The identified top hits were further evaluated through MD simulations followed by the binding free energy calculations using MM-GBSA. Interestingly, in our screening, several promising drugs stand out as potential inhibitors of Mpro. However, based on control (N3 and 13b), we have identified six potential molecules, Leupeptin Hemisulphate, Pepstatin A, Nelfinavir, Birinapant, Lypression and Octreotide which have shown the reasonably significant MM-GBSA score. Further insight shows that the molecules form stable interactions with hot-spot residues, that are mainly conserved and can be targeted for structure- and pharmacophore-based designing. The pharmacokinetic annotations and therapeutic importance have suggested that these molecules possess drug-like properties and pave their way for in-vitro studies.Communicated by Ramaswamy H. Sarma.