Molecular docking studies of Indian variants of pathophysiological proteins of SARS-CoV-2 with selected drug candidates.
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ABSTRACT:
SUBMITTER: Sridhar S
PROVIDER: S-EPMC8435403 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:The earth has witnessed the greatest global health crisis due to the outbreak of the SARS-CoV-2 virus in late 2019, resulting in the pandemic COVID-19 with 3.38 million mortality and 163 million infections across 222 nations. Therefore, there is an urgent need for an effective therapeutic option against the SARS-CoV-2 virus. Transition metal complexes with unique chemical, kinetic and thermodynamic properties have recently emerged as the viable alternative for medicinal applications. Herein, the potential application of selected antiviral transition metal-based compounds against the SARS-CoV-2 virus was explored in silico. Initially, the transition metal-based antiviral compounds (1-5) were identified based on the structural similarity of the viral proteins (proteases, reverse transcriptase, envelop glycoproteins, etc.) of HIV, HCV, or Influenza virus with the proteins (S-protein, RNA-dependent RNA polymerase, proteases, etc) of SARS-CoV-2 virus. Hence the complexes (1-5) were subjected to ADME analysis for toxicology and pharmacokinetics report and further for the molecular docking calculations, selectively with the viral proteins of the SARS-CoV-2 virus. The molecular docking studies revealed that the iron-porphyrin complex (1) and antimalarial drug, ferroquine (2) could be the potential inhibitors of Main protease (Mpro) and spike proteins respectively of SARS-CoV-2 virus. The complex 1 exhibited high binding energy of -11.74 kcal/mol with the Mpro of SARS-CoV-2. Similarly ferroquine exhibitred binding energy of -7.43 kcal/mol against spike protein of SARS-CoV-2. The complex 5 also exhibited good binding constants values of -7.67, -8.68 and -7.82 kcal/mol with the spike protein, Mpro and RNA dependent RNA polymerase (RdRp) proteins respectively. Overall, transition metal complexes could provide an alternative and viable therapeutic solution for COVID-19.
| S-EPMC8441708 | biostudies-literature
Project description:Background: COVID-19 has become a global threat. Since its first outbreak from Wuhan, China in December 2019, the SARS-CoV-2 virus has gone through structural changes arising due to mutations in its surface glycoprotein. These mutations have led to the emergence of different genetic variants threatening public health due to increased transmission and virulence. As new drug development is a long process, repurposing existing antiviral drugs with potential activity against SARS-CoV-2 might be a possible solution to mitigate the current situation. Methods: This study focused on utilizing molecular docking to determine the effect of potential drugs on several variants of concern (VOCs). The effect of various drugs such as baricitinib, favipiravir, lopinavir, remdesivir and dexamethasone, which might have the potential to treat SARS-CoV-2 infections as evident from previous studies, was investigated for different VOCs. Results: Remdesivir showed promising results for B.1.351 variant (binding energy: -7.3 kcal/mol) with residues Gln319 and Val503 facilitating strong binding. Favipiravir showed favorable results against B.1.1.7 (binding energy: -5.6 kcal/mol), B.1.351 (binding energy: -5.1 kcal/mol) and B.1.617.2 (binding energy: -5 kcal/mol). Molecular dynamics simulation for favipiravir/B.1.1.7 was conducted and showed significant results in agreement with our findings. Conclusions: From structural modeling and molecular docking experiments, it is evident that mutations outside the receptor binding domain of surface glycoprotein do not have a sharp impact on drug binding affinity. Thus, the potential use of these drugs should be explored further for their antiviral effect against SARS-CoV-2 VOCs.
| S-EPMC9445560 | biostudies-literature
Project description:The ongoing COVID-19 pandemic represents an unprecedented global health crisis. Here, we report the identification of a synthetic nanobody (sybody) pair, Sb#15 and Sb#68, that can bind simultaneously to the SARS-CoV-2 spike-RBD and efficiently neutralize pseudotyped and live-viruses by interfering with ACE2 interaction. Cryo-EM confirms that Sb#15 and Sb#68 engage two spatially-discrete epitopes, influencing rational design of bispecific and tri-bispecific fusion constructs that exhibit up to 100- and 1000-fold increase in neutralization potency, respectively. Cryo-EM of the sybody-spike complex additionally reveals a novel up-out RBD conformation. While resistant viruses emerge rapidly in the presence of single binders, no escape variants are observed in presence of the bispecific sybody. The multivalent bispecific constructs further increase the neutralization potency against globally-circulating SARS-CoV-2 variants of concern. Our study illustrates the power of multivalency and biparatopic nanobody fusions for the potential development of therapeutic strategies that mitigate the emergence of new SARS-CoV-2 escape mutants.
| S-SCDT-EMBOR-2021-54199V1 | biostudies-other
Project description:Coronavirus disease 2019 (COVID-19) pandemic, caused by the Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) is one of the major health threats the world has experienced. In order to stem the tide of the virus and its associated disease, rapid efforts have been dedicated to identifying credible anti-SARS-CoV-2 drugs. This study forms part of the continuing efforts to develop anti-SARS-CoV-2 molecules and employed a computational structure-activity relationship approach with emphasis on 99 plant secondary metabolites from eight selected African medicinal plants with proven therapeutic benefits against respiratory diseases focusing on the viral protein targets [Spike protein (Sgp), Main protease (Mpro), and RNA-dependent RNA polymerase (RdRp)]. The results of the molecular dynamics simulation of the best docked compounds presented as binding free energy revealed that three compounds each against the Sgp (VBS, COG and ABA), and Mpro (COR, QOR and ABG) had higher and better affinity for the proteins than the respective reference drugs, cefoperazone (CSP) and Nelfinavir (NEF), while four compounds (HDG, VBS, COR and KOR) had higher and favorable binding affinity towards RdRp than the reference standard, ramdesivir (RDS). Analysis of interaction with the receptor binding domain amino acid residues of Sgp showed that VBS had the highest number of interactions (17) relative to 14 and 13 for COG and ABA, respectively. For Mpro, COR showed interactions with catalytic dyad residues (His172 and Cys145). Compared to RDS, COR, HDG, VBS and KOR formed 19, 18, 17 and 12 H-bond and Van der Waal bonds, respectively, with RdRp. Furthermore, structural examination of the three proteins after binding to the lead compounds revealed that the compounds formed stable complexes. These observations suggest that the identified compounds might be beneficial in the fight against COVID-19 and are suggested for further in vitro and in vivo experimental validation.
| S-EPMC9279166 | biostudies-literature
Project description:RNA-seq analysis was applied to examine the mock or SARS-CoV-2 infected DA neurons.We found SARS-CoV-2 infection caused DA neurons senescence.We also found several drug candidates block SARS-CoV-2 infection caused senescence of hPSC-derived DA neurons. RNA-seq was applied to analyze the drug candidates or DMSO treated DA neurons upon SARS-CoV-2 infection. The genes involved in senescence pathway were rescued in riluzole, metformin or imatinib treated DA neurons.
2022-10-01 | GSE156761 | GEO
Project description:The emerged Coronavirus disease (COVID-19) causes severe or even fatal respiratory tract infection, and to date there is no FDA-approved therapeutics or effective treatment available to effectively combat this viral infection. This urgent situation is an attractive research area in the field of drug design and development. One of the most important targets of SARS-coronavirus-2 (SARS Cov-2) is the main protease (3CLpro). Actinomycetes are important resources for drug discovery. The angucylines that are mainly produced by Streptomyces genus of actinomycetes exhibit a broad range of biological activities such as anticancer, antibacterial and antiviral. This study aims to investigate the binding affinity and molecular interactions of 157 available angucycline compounds with 3CLpro using docking and molecular dynamics simulations. MM-PBSA calculations showed that moromycin A has a better binding energy (- 30.42 kcal mol-1) compared with other ligands (in a range of - 18.66 to - 22.89 kcal mol-1) including saquayamycin K4 (- 21.27 kcal mol-1) except the co-crystallized ligand N3. However, in vitro and in vivo studies are essential to assess the effectiveness of angucycline compounds against coronavirus.
| S-EPMC8035615 | biostudies-literature
Project description:Presently world is on a war with the novel coronavirus and with no immediate treatments available the scourge caused by the SARS-CoV-2 is increasing day by day. A lot of researches are going on for the potential drug candidate that could help the healthcare system in this fight. Plants are a natural data bank of bioactive compounds. Many phytochemicals are being studied for various ailments including cancer, bacterial and viral infections, etc. The present study aims to screen 38 bioactive compounds from 5 selected plants viz., Azadirachta indica, Curcuma longa, Zingiber officinale, Ocimum basilicum and Panax ginseng against SARS-CoV-2. Lipinski's rule was taken as the foundation for initial screening. Shortlisted compounds were subjected to molecular docking study with Mpro receptor present in SARS-CoV-2. The study identified that gedunin, epoxyazadiradione, nimbin and ginsenosides have potential to inhibit Mpro activity and their binding energies are - 9.51 kcal/mol, - 8.47 kcal/mol, - 8.66 kcal/mol and - 9.63 kcal/mol respectively. Based on bioavailability radar studies gedunin and epoxyazadiradione are the two most potent compounds which are used for molecular dynamics simulation studies. Molecular dynamics studies showed that gedunin is more potent than epoxyazadiradione. To find the effectiveness and to propose the exact mechanism, in-vitro studies can be further performed on gedunin.
| S-EPMC7567421 | biostudies-literature
Project description:An outbreak of a cluster of viral pneumonia cases, subsequently identified as coronavirus disease 2019 (COVID-19), due to a novel SARS-CoV-2 necessitates an urgent need for a vaccine to prevent infection or an approved medication for a cure. In our in silico molecular docking study, a total of 173 compounds, including FDA-approved antiviral drugs, with good ADME descriptors, and some other nucleotide analogues were screened. The results show that these compounds demonstrate strong binding affinity for the residues at the active sites of RNA-dependent RNA-polymerase (RdRp) modelled structures and Chymotrypsin-like cysteine protease (3CLpro) of the HCoV proteins. Free energies (ΔG's) of binding for SARS-CoV-2 and SARS-CoV RdRp range from - 5.4 to - 8.8 kcal/mol and - 4.9 to - 8.7 kcal/mol, respectively. Also, SARS-CoV-2 and SARS-CoV 3CLpro gave ΔG values ranging from - 5.1 to - 8.4 kcal/mol and - 5.5 to - 8.6 kcal/mol, respectively. Interesting results are obtained for ivermectin, an antiparasitic agent with broad spectrum activity, which gave the highest binding energy value (- 8.8 kcal/mol) against the 3CLpro of SARS-CoV-2 and RdRps of both SARS-CoV and SARS-CoV-2. The reason for such high binding energy values is probably due to the presence of hydroxy, methoxy and sugar moieties in its structure. The stability of the protein-ligand complexes of polymerase inhibitors considered in this investigation, such as Sofosbuvir, Remdesivir, Tenofovir, Ribavirin, Galidesivir, 5c3, 5h1 and 7a1, show strong to moderate hydrogen bonding and hydrophobic interactions (π-π stacked, π-π T-shaped, π-sigma and π-alkyl). The stability provided from such interactions translate into greater antiviral activity or inhibitory effect of the ligands. Assessment of the average free energies of binding of the FDA approved drugs are highly comparable for conformers of a particular inhibitor, indicating similar modes of binding within the pockets.Supplementary informationThe online version contains supplementary material available at 10.1007/s13721-021-00299-2.
| S-EPMC7992627 | biostudies-literature
Project description:The COVID-19 pandemic has been responsible for several deaths worldwide. The causative agent behind this disease is the Severe Acute Respiratory Syndrome - novel Coronavirus 2 (SARS-CoV-2). SARS-CoV-2 belongs to the category of RNA viruses. The main protease, responsible for the cleavage of the viral polyprotein is considered as one of the hot targets for treating COVID-19. Earlier reports suggest the use of HIV anti-viral drugs for targeting the main protease of SARS-CoV, which caused SARS in the year 2002-2003. Hence, drug repurposing approach may prove to be useful in targeting the main protease of SARS-CoV-2. The high-resolution crystal structure of the main protease of SARS-CoV-2 (PDB ID: 6LU7) was used as the target. The Food and Drug Administration approved and SWEETLEAD database of drug molecules were screened. The apo form of the main protease was simulated for a cumulative of 150 ns and 10 μs open-source simulation data was used, to obtain conformations for ensemble docking. The representative structures for docking were selected using RMSD-based clustering and Markov State Modeling analysis. This ensemble docking approach for the main protease helped in exploring the conformational variation in the drug-binding site of the main protease leading to the efficient binding of more relevant drug molecules. The drugs obtained as top hits from the ensemble docking possessed anti-bacterial and anti-viral properties. This in silico ensemble docking approach would support the identification of potential candidates for repurposing against COVID-19. Communicated by Ramaswamy H. Sarma.
| S-EPMC7441806 | biostudies-literature
Project description:In a short time, the COVID-19 pandemic has left the world with over 25 million cases and staggering death tolls that are still rising. Treatments for SARS-CoV-2 infection are desperately needed as there are currently no approved drug therapies. With limited knowledge of viral mechanisms, a network controllability method of prioritizing existing drugs for repurposing efforts is optimal for quickly moving through the drug approval pipeline using limited, available, virus-specific data. Based on network topology and controllability, 16 proteins involved in translation, cellular transport, cellular stress, and host immune response are predicted as regulators of the SARS-CoV-2 infected cell. Of the 16, eight are prioritized as possible drug targets where two, PVR and SCARB1, are previously unexplored. Known compounds targeting these genes are suggested for viral inhibition study. Prioritized proteins in agreement with previous analysis and viral inhibition studies verify the ability of network controllability to predict biologically relevant candidates.
| S-EPMC7650805 | biostudies-literature