Protein Structure and Function Prediction of SARS-CoV 2: Prospective Antivirus Active Drug Binding Sites (original) (raw)
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Coronaviruses, 2021
Background: The discovery of a novel strain of coronavirus in 2019 (COVID-19) has triggered a series of tragic events in the world with thousands of deaths recorded daily. Despite the huge resources committed to the discovery of vaccines against this highly pathogenic virus, scientists are still unable to find suitable treatments for the disease. Understanding the structure of coronavirus proteins could provide a basis for the development of cheap, potent and, less toxic vaccines. Objective: This study was therefore designed to model coronavirus spike (S) glycoprotein and envelope (E) protein as well as to carry out molecular docking of potential drugs to the homologs and coronavirus main protease (Mpro). Methods: Homology modeling of coronavirus spike (S) glycoprotein and envelope (E) protein was carried out using sequence deposited in the Uniprot database. The topological features of the model’s catalytic site were evaluated using the CASTp server. Compounds reported as potential ...
arXiv: Biomolecules, 2020
SARS-CoV-2, the causative agent of the disease known as Covid-19, has so far reported around 3,435,000 cases of human infections, including more than 239,000 deaths in 187 countries, with no effective treatment currently available. For this reason, it is necessary to explore new approaches for the development of a drug capable of inhibiting the entry of the virus into the host cell. Therefore, this work includes the exploration of potential inhibitory compounds for the Spike protein of SARS-CoV-2 (PDB ID: 6VSB), which were obtained from The Patogen Box. Later, they were filtered through virtual screening and molecular docking techniques, thus obtaining a top of 1000 compounds, which were used against a binding site located in the Receptor Binding Domain (RBD) and a cryptic site located in the N-Terminal Domain (NTD), resulting in good pharmaceutical targets for the blocking the infection. From the top 1000, the best compound (TCMDC-124223) was selected for the binding site. It inter...
International Journal for Research in Applied Science & Engineering Technology, 2021
The coronavirus outbreak in recent times has created a terrific pandemic situation in the universe. We aim to identify the specific domain in the viral particle responsible for binding into the host cell and for finding any anti-viral drug that could inhibit the binding interaction. Using pharmacophore-based drug modelling for drug molecule that can inhibit the spike protein interaction is targeted. Spike protein of a viral body (SARS-CoV-2) represents a structure that acts as the ligand that binds with the host, made up of several repeats of Beta sheets acts as the substrate-binding domain part. The anti-viral drug or the antibody inhibit the interaction between the spike and the receptor, are predicted via receptor-ligand interaction of the desired or predictable drug molecule. Common and trusted anti-viral strategies directed to S-protein consist of mitigation of host recognition by acting on S1-RBD (Spike Protein Receptor Binding Domain) coupled with inhibition of fusion process by acting at the level of S2 sub-unit has been explored. Drugs like Favipiravir and Barcitinib are in use to reduce viral entry in the host cells, along with several developing vaccines.
Structure and dynamics of membrane protein in SARS-CoV-2
Journal of Biomolecular Structure and Dynamics
SARS-CoV-2 membrane (M) protein performs a variety of critical functions in virus infection cycle. However, the expression and purification of membrane protein structure is difficult despite tremendous progress. In this study, the 3 D structure is modeled followed by intensive validation and molecular dynamics simulation. The lack of suitable homologous templates (>30% sequence identities) leads us to construct the membrane protein models using template-free modeling (de novo or ab initio) approach with Robetta and trRosetta servers. Comparing with other model structures, it is evident that trRosetta (TM-score: 0.64; TM region RMSD: 2 Å) can provide the best model than Robetta (TMscore: 0.61; TM region RMSD: 3.3 Å) and I-TASSER (TM-score: 0.45; TM region RMSD: 6.5 Å). 100 ns molecular dynamics simulations are performed on the model structures by incorporating membrane environment. Moreover, secondary structure elements and principal component analysis (PCA) have also been performed on MD simulation data. Finally, trRosetta model is utilized for interpretation and visualization of interacting residues during protein-protein interactions. The common interacting residues including Phe103, Arg107, Met109, Trp110, Arg131, and Glu135 in the C-terminal domain of M protein are identified in membrane-spike and membrane-nucleocapsid protein complexes. The active site residues are also predicted for potential drug and peptide binding. Overall, this study might be helpful to design drugs and peptides against the modeled membrane protein of SARS-CoV-2 to accelerate further investigation.
2020
Angiotensin converting enzyme 2 (ACE2) (EC:3.4.17.23) is a transmembrane protein which is considered as receptor for spike protein binding of novel coronavirus (SARS-CoV2). Since no specific medication is available to treat COVID-19, designing of new drug is important and essential. In this regard, in silico method plays an important role as it is rapid, cost effective, compared to the trial and error methods using experimental studies. Natural products are safe and easily available to treat coronavirus effected patients, in the present alarming situation. In this paper five phytochemicals which belong to flavonoid and anthraquinone subclass, selected as small molecules in molecular docking study of spike protein of SARS-CoV2 with its human receptor ACE2 molecule. From the detail analysis of their molecular binding site on spike protein binding site with its receptor, hesperidin, emodin and chrysin are selected as competent natural products from both Indian and Chinese medicinal pla...
Modeling novel Anti-Viral peptides (AVPs) with in-silico docking simulations against corona virus
Materials Today: Proceedings, 2021
The havoc created by Corona virus has been dealt with using various integrative approaches adopted by laboratories throughout the world. Use of anti-viral peptides (AVPs) although new but has shown tremendous potential against many pathogens. Previously AVPs have been designed against spike protein of corona virus which is the major entry mediating molecule. Using various in-silico strategies, in this research work AVPs have been modeled against lesser studied viral proteins namely ORF7a protein, Envelope protein (E), Nucleoprotein (N), and Non-Structural protein (Nsp1 and Nsp2). The predicted AVPs have been docked against various host as well as viral proteins. The interaction of small AVPs seems capable of interfering with binding between viral protein and its host counterpart. Therefore, these AVPs can act as a deterrent against novel corona virus, which requires further validation through laboratory techniques.
2020
BackgroundThe current Novel Coronavirus (SARS-CoV-2) pandemic is the third major outbreak of the 21st century which emerged in December 2019 from Wuhan, China. At present there are no known treatments or vaccines to cure or prevent the illness.ObjectiveThe objective of this study was to explore a list of potential drugs (herbal and antivirals) for their role in inhibiting activity and or replication of SARS-CoV-2 by using molecular docking onto the crystal structures of key viral proteins.MethodologyIn this study, we used molecular docking to estimate the binding affinities of 3699 drugs on the potential active sites of the 6 main SARS-CoV-2 proteins (Papain like protease, Main protease, ADP Ribose phosphatase, Spike protein, NSP-9 and NSP-10 to 16 complex). While other studies have mostly been performed on the homology models, we obtained the most recently submitted crystal structures of all 6 proteins from the protein data bank for this analysis.ResultsOur results showed the top l...
Severe acute respiratory syndrome coronavirus (SARS-CoV-2) is an emerging new viral pathogen that causes severe respiratory disease. SARS-CoV-2 is responsible for an outbreak of COVID-19 pandemic worldwide. As there are no confirmed antiviral drugs or vaccines currently available for the treatment of COVID-19, discovering potent inhibitors or vaccines are urgently required for the benefit of humanity. The glycosylated Spike protein (S-protein) directly interacts with human angiotensin-converting enzyme 2 (ACE2) receptor through the receptor-binding domain (RBD) of S-protein. As the S-protein is exposed to the surface and is essential for entry into the host, the S-protein can be considered as a first-line therapeutic target for antiviral therapy and vaccine development. In-silico screening, docking and molecular dynamics simulation studies were performed to identify repurposing drugs using DrugBank and PubChem library against the RBD of S-protein. The study identified a laxative dru...
Proceedings of ISEHT – 2012, VSU, Nellore, India
Severe acute respiratory syndrome (SARS) is an acute respiratory disease caused by a newly identified coronavirus (SARS-CoV). Recently a new mechanism for entry of SARS CoV into target cells was reported. The entry of SARS-CoV requirements for proteases in activation of viral infectivity. Cathepsin -L (CTSL) is the primary enzyme involved in entry of virus. Inhibition of CTSL represents a potential drug target for SARS disease. MDL28170 (CID 10152654) was identified as an efficient natural inhibitor of CTSL mediated substrate cleavage. Based on the ligand structure similarity to obtain similar potent drug like molecules, the PubChem Database was screened for similar potent drug like compounds as MDL28170. Virtual Screening and docking studies were performed for these molecules against CTSL protein using PyRxVirtual Screening tool and Auto Dock Vena. The docking results showed that the compounds 11496895, 333247, 11795833 and 501956 were having highest binding energies like -8.6, -8.5, -8.5, and -8.4. The present study indicates that the lead molecules have to be evaluated further for better potential drug molecules. 1961-66. Simmons G, Gosalia DN, Rennekamp AJ, Reeves JD, Diamond SL, and Bates P (2005) Inhibitors of cathepsin L prevent severe acute respiratory syndrome coronavirus entry. Proc Natl Acad Sci USA 102:11876-11881. Thiel, V., (2007). Coronaviruses: Molecular and Cellular Biology (1st ed.). Caister Academic Press. 978-1-904455-16-5.
The receptor-binding domain (RBD) of SARS-CoV-2 spike (S) protein plays a vital role in binding and internalization through the alpha-helix (AH) of human angiotensin-converting enzyme 2 (hACE2). Thus, it is a potential target for designing and developing antiviral agents. Inhibition of RBD activity of the S protein may be achieved by blocking RBD interaction with hACE2. In this context, inhibitors with large contact surface area are preferable as they can form a potentially stable complex with RBD of S protein and would not allow RBD to come in contact with hACE2. Peptides represent excellent features as potential anti-RBD agents due to better efficacy, safety, and tolerability in humans compared to that of small molecules. The present study has selected 645 antiviral peptides known to inhibit various viruses and computationally screened them against the RBD of SARS-CoV-2 S protein. In primary screening, 27 out of 645 peptides exhibited higher affinity for the RBD of S protein compared to that of AH of the hACE2 receptor. Subsequently, AVP1795 appeared as the most promising candidate that could inhibit hACE2 recognition by SARS-CoV 2 as was predicted by the molecular dynamics simulation. The critical residues in RBD found for protein-peptide interactions are TYR 489, GLY 485, TYR 505, and GLU 484. Peptide-protein interactions were substantially influenced by hydrogen bonding and hydrophobic interactions. This comprehensive computational screening may provide a guideline to design the most effective peptides targeting the spike protein, which could be studied further in vitro and in vivo for assessing their anti-SARS CoV-2 activity.