Molecules against Covid-19: An in silico approach for drug development
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ABSTRACT:
SUBMITTER: Bharti R
PROVIDER: S-EPMC7946544 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:The importance of coronaviruses as human pathogen has been highlighted by the recent outbreak of SARS-CoV-2 leading to the search of suitable drugs to overcome respiratory infections caused by the virus. Due to the lack of specific drugs against coronavirus, the existing antiviral and antimalarial drugs are currently being administered to the patients infected with SARS-CoV-2. The scientists are also considering repurposing of some of the existing drugs as a suitable option in search of effective drugs against coronavirus till the establishment of a potent drug and/or vaccine. Computer-aided drug discovery provides a promising attempt to enable scientists to develop new and target specific drugs to combat any disease. The discovery of novel targets for COVID-19 using computer-aided drug discovery tools requires knowledge of the structure of coronavirus and various target proteins present in the virus. Targeting viral proteins will make the drug specific against the virus, thereby, increasing the chances of viral mortality. Hence, this review provides the structure of SARS-CoV-2 virus along with the important viral components involved in causing infection. It also focuses on the role of various target proteins in disease, the mechanism by which currently administered drugs act against the virus and the repurposing of few drugs. The gap arising from the absence of specific drugs is addressed by proposing potential antiviral drug targets which might provide insights into structure-based drug development against SARS-CoV-2.
| S-EPMC7438372 | biostudies-literature
Project description:The COVID-19 pandemic has caused unprecedented health and economic crisis throughout the world. However, there is no effective medication or therapeutic strategy for treatment of this disease currently. Here, to elucidate the inhibitory effects, we first tested binding affinities of 11 HIV-1 protease inhibitors or their pharmacoenhancers docked onto SARS-CoV-2 main protease (M pro ), and 12 nucleotide-analog inhibitors docked onto RNA dependent RNA polymerase (RdRp). To further obtain the effective drug candidates, we screened 728 approved drugs via virtual screening on SARS-CoV-2 M pro . Our results demonstrate that remdesivir shows the best binding energy on RdRp and saquinvir is the best inhibitor of M pro . Based on the binding energies, we also list 10 top-ranked approved drugs which can be potential inhibitors for M pro . Overall, our results do not only propose drug candidates for further experiments and clinical trials but also pave the way for future lead optimization and drug design.
| S-EPMC7574721 | biostudies-literature
Project description:COVID-19 pathogenesis is mainly attributed to dysregulated antiviral immune response, the prominent hallmark of COVID-19. As no established drugs are available against SARS-CoV-2 and developing new ones would be a big challenge, repurposing of existing drugs holds promise against COVID-19. Here, we used a signature-based strategy to delve into cellular responses to SARS-CoV-2 infection in order to identify potential host contributors in COVID-19 pathogenesis and to find repurposable drugs using in silico approaches. We scrutinized transcriptomic profile of various human alveolar cell sources infected with SARS-CoV-2 to determine up-regulated genes specific to COVID-19. Enrichment analysis revealed that the up-regulated genes were involved mainly in viral infectious disease, immune system, and signal transduction pathways. Analysis of protein-protein interaction network and COVID-19 molecular pathway resulted in identifying several anti-viral proteins as well as 11 host pro-viral proteins, ADAR, HBEGF, MMP9, USP18, JUN, FOS, IRF2, ICAM1, IFI35, CASP1, and STAT3. Finally, molecular docking of up-regulated proteins and all FDA-approved drugs revealed that both Hydrocortisone and Benzhydrocodone possess high binding affinity for all pro-viral proteins. The suggested repurposed drugs should be subject to complementary in vitro and in vivo experiments in order to be evaluated in detail prior to clinical studies in potential management of COVID-19.
| S-EPMC9212771 | biostudies-literature
Project description:AimsThe severe acute respiratory syndrome coronavirus 2, better known as COVID-19 has become the current health concern to the entire world. Initially appeared in Wuhan, China around December 2019, it had spread to almost 187 countries due to its high contagious nature. Precautionary measures remain the sole obliging tactic to cease the person to person transmissions till any effective method of treatment or vaccine is developed. Amidst the pandemic, research and development of new molecule is labour-intensive and tedious process. Drug repurposing is the concept of identifying therapeutically potent molecule from the library of pre-existing molecules.Materials and methodsIn the present study, 61 molecules that are already being used in clinics or under clinical scrutiny as antiviral agents are surveyed via docking study. Docking study was performed using Maestro interface (Schrödinger Suite, LLC, NY).Key findingsOut of these 61 molecules, 37 molecules were found to interact with >2 protein structures of COVID-19. The docking results indicate that amongst the reported molecules, HIV protease inhibitors and RNA-dependent RNA polymerase inhibitors showed promising features of binding to COVID-19 enzyme. Along with these, Methisazone an inhibitor of protein synthesis, CGP42112A an angiotensin AT2 receptor agonist and ABT450 an inhibitor of the non-structural protein 3-4A might become convenient treatment option as well against COVID-19.SignificanceThe drug repurposing approach provide an insight about the therapeutics that might be helpful in treating corona virus disease.
| S-EPMC7194845 | biostudies-literature
Project description:In an emergency, drug repurposing is the best alternative option against newly emerged severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection. However, several bioactive natural products have shown potential against SARS-CoV-2 in recent studies. The present study selected sixty-eight broad-spectrum antiviral marine terpenoids and performed molecular docking against two novel SARS-CoV-2 enzymes (main protease or Mpro or 3CLpro) and RNA-dependent RNA polymerase (RdRp). In addition, the present study analysed the physiochemical-toxicity-pharmacokinetic profile, structural activity relationship, and phylogenetic tree with various computational tools to select the 'lead' candidate. The genomic diversity study with multiple sequence analyses and phylogenetic tree confirmed that the newly emerged SARS-CoV-2 strain was up to 96% structurally similar to existing CoV-strains. Furthermore, the anti-SARS-CoV-2 potency based on a protein-ligand docking score (kcal/mol) exposed that the marine terpenoid brevione F (-8.4) and stachyflin (-8.4) exhibited similar activity with the reference antiviral drugs lopinavir (-8.4) and darunavir (-7.5) against the target SARS-CoV-Mpro. Similarly, marine terpenoids such as xiamycin (-9.3), thyrsiferol (-9.2), liouvilloside B (-8.9), liouvilloside A (-8.8), and stachyflin (-8.7) exhibited comparatively higher docking scores than the referral drug remdesivir (-7.4), and favipiravir (-5.7) against the target SARS-CoV-2-RdRp. The above in silico investigations concluded that stachyflin is the most 'lead' candidate with the most potential against SARS-CoV-2. Previously, stachyflin also exhibited potential activity against HSV-1 and CoV-A59 within IC50, 0.16-0.82 µM. Therefore, some additional pharmacological studies are needed to develop 'stachyflin' as a drug against SARS-CoV-2.
| S-EPMC8614725 | biostudies-literature
Project description:Understanding the immunological behavior of COVID-19 cases at molecular level is essential for therapeutic development. In this study, multi-omics and systems pharmacology analyses were performed to unravel the multi-targeted mechanisms of novel bioactives to combat COVID-19. Immuno-transcriptomic dataset of healthy controls and COVID-19 cases was retrieved from ArrayExpress. Phytocompounds from ethnobotanical plants were collected from PubChem. Differentially expressed 98 immune genes associated with COVID-19 were derived through NetworkAnalyst 3.0. Among 259 plant derived compounds, 154 compounds were targeting 13 COVID-19 immune genes involved in diverse signaling pathways. In addition, pharmacological properties of these phytocompounds were compared with COVID-19 drugs prescribed by WHO, and 25 novel phytocompounds were found to be more efficient with higher bioactive scores. The current study unravels the virogenomic signatures which can serve as therapeutic targets and identified phytocompounds with anti-COVID-19 efficacy. However, further experimental validation is essential to bring out these molecules as commercial drug candidates.
| S-EPMC7410791 | biostudies-literature
Project description:The life challenging COVID-19 disease caused by the SARS-CoV-2 virus has greatly impacted smooth survival worldwide since its discovery in December 2019. Currently, it is one of the major threats to humanity. Moreover, any specific drug or vaccine unavailability against COVID-19 forces to discover a new drug on an urgent basis. Viral cycle inhibition could be one possible way to prevent the further genesis of this viral disease, which can be contributed by drug repurposing techniques or screening of small bioactive natural molecules against already validated targets of COVID-19. The main protease (Mpro) responsible for producing functional proteins from polyprotein is an important key step for SARS-CoV-2 virion replication. Natural product or herbal based formulations are an important platform for potential therapeutics and lead compounds in the drug discovery process. Therefore, here we have screened >53,500 bioactive natural molecules from six different natural product databases against Mpro (PDB ID: 6LU7) of COVID-19 through computational study. Further, the top three molecules were subjected to pharmacokinetics evaluation, which is an important factor that reduces the drug failure rate. Moreover, the top three screened molecules (C00014803, C00006660, ANLT0001) were further validated by a molecular dynamics study under a condition similar to the physiological one. Relative binding energy analysis of three lead molecules indicated that C00014803 possess highest binding affinity among all three hits. These extensive studies can be a significant foundation for developing a therapeutic agent against COVID-19 through vet lab studies.
| S-EPMC8042570 | biostudies-literature
Project description: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.
| S-EPMC7256355 | biostudies-literature
Project description:The entire human population over the globe is currently facing appalling conditions due to the spread of infection from coronavirus disease-2019 (COVID-19). The spike glycoprotein of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) present on the surface of the virion mediates the virus entry into the host cells and therefore is targeted by several scientific groups as a novel drug target site. The spike glycoprotein binds to the human angiotensin-converting enzyme-2 (hACE2) cell surface receptor abundantly expressed in lung tissues, and this binding phenomenon is a primary determinant of cell tropism and pathogenesis. The binding and internalization of the virus is the primary and most crucial step in the process of infection, and therefore the molecules targeting the inhibition of this process certainly hold a significant therapeutic value. Thus, we systematically applied the computational techniques to identify the plausible inhibitor from a chosen set of well characterized diaryl pyrimidine analogues which may disrupt interfacial interaction of spike glycoprotein (S) at the surface of hACE2. Using molecular docking, molecular dynamics (MD) simulation and binding free energy calculation, we have identified AP-NP (2-(2-amino-5-(naphthalen-2-yl)pyrimidin-4-yl)phenol), AP-3-OMe-Ph (2-(2-amino-5-(3-methoxyphenyl)pyrimidin-4-yl)phenol) and AP-4-Me-Ph (2-(2-amino-5-(p-tolyl) pyrimidin-4-yl)phenol) from a group of diaryl pyrimidine derivatives which appears to bind at the interface of the hACE2-S complex with low binding free energy. Thus, pyrimidine derivative AP-NP may be explored as an effective inhibitor for hACE2-S complex. Furthermore, in vitro and in vivo studies will strengthen the use of these inhibitors as suitable drug candidates against SARS-COV-2. Communicated by Ramaswamy H. Sarma.
| S-EPMC7441775 | biostudies-literature
Project description:BackgroundThe recent severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection cause high mortality and there is an emergency need to develop a specific drug to treat the novel coronavirus disease, COVID-19. However, some natural and synthetic products with action against SARS-CoV-2 have been reported in recent research, there is no specific drug available for treating COVID-19. In the present study, molecular interaction analysis was performed for 16 semisynthetic andrographolides (AGP) against 5 SARS-CoV-2 enzymes main protease (Mpro, PDB: 6LU7), papain-like protease (PLpro, PDB: 6WUU), spike glycoprotein (S, PDB: 6VXX), NSP15 endoribonuclease (NSP15, PDB: 6VWW), and RNA-dependent RNA polymerase (RdRp, PDB: 6M71). Moreover, the compounds pharmacokinetic and toxic profiles were also analyzed using computational tools.ResultsThe protein-ligand docking score (kcal/mol) revealed that all the tested AGP derivatives showed a better binding affinity towards all the tested enzymes than hydroxychloroquine (HCQ). Meanwhile, all the tested AGP derivatives showed a better binding score with RdRp and S than remdesivir (REM). Interestingly, compounds 12, 14, and 15 showed a better binding affinity towards the all the tested enzyme than AGP, REM, and HCQ. AGP-16 had shown - 8.7 kcal/mol binding/docking score for Mpro, AGP-15 showed - 8.6 kcal/mol for NSP15, and AGP-10, 13, and 15 exhibited - 8.7, - 8.9, and - 8.7 kcal/mol, respectively, for S.ConclusionOverall results of the present study concluded that AGP derivatives 14 and 15 could be the best 'lead' candidate for the treatment against SARS-CoV-2 infection. However, molecular dynamic studies and pharmacological screenings are essential to developing AGP derivatives 14 and 15 as a drug against COVID-19.
| S-EPMC9008396 | biostudies-literature