Targeting Virus-Host Interaction: An in Silico Approach to Develop Promising Inhibitors Against COVID-19 (original) (raw)
Related papers
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...
Acta Pharmacologica Sinica
Coronavirus disease 2019 is a newly emerging infectious disease currently spreading across the world. It is caused by a novel coronavirus, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The spike (S) protein of SARS-CoV-2, which plays a key role in the receptor recognition and cell membrane fusion process, is composed of two subunits, S1 and S2. The S1 subunit contains a receptor-binding domain that recognizes and binds to the host receptor angiotensin-converting enzyme 2, while the S2 subunit mediates viral cell membrane fusion by forming a six-helical bundle via the two-heptad repeat domain. In this review, we highlight recent research advance in the structure, function and development of antivirus drugs targeting the S protein.
Design and Identification of Inhibitors for the Spike-ACE2 Target of SARS-CoV-2
International Journal of Molecular Sciences
When an epidemic started in the Chinese city of Wuhan in December 2019, coronavirus was identified as the cause. Infection by the virus occurs through the interaction of viral S protein with the hosts’ angiotensin-converting enzyme 2. By leveraging resources such as the DrugBank database and bioinformatics techniques, ligands with potential activity against the SARS-CoV-2 spike protein were designed and identified in this investigation. The FTMap server and the Molegro software were used to determine the active site of the Spike-ACE2 protein’s crystal structure. Virtual screening was performed using a pharmacophore model obtained from antiparasitic drugs, obtaining 2000 molecules from molport®. The ADME/Tox profiles were used to identify the most promising compounds with desirable drug characteristics. The binding affinity investigation was then conducted with selected candidates. A molecular docking study showed five structures with better binding affinity than hydroxychloroquine. ...
Dr. Sulaiman Al Habib Medical Journal, 2021
The SARS-CoV-2-induced novel coronavirus disease has become a global pandemic. As the latest coronavirus variants are even more infectious and deadly, its treatment is very difficult. Currently used drugs such as remdesivir, saquinavir, and chloroquine have several drawbacks. Recent studies have reported key proteins that could serve as drug targets. Amongst them, the spike (S) glycoprotein is an attractive drug target that plays a prominent role in viral binding and entry. With the aim of targeting and blocking the S protein, we designed a computational study for screening novel antiviral compounds. Molecular docking was used as a screening tool, and Molecular Dynamics (MD) simulations were used to further confirm the stability of ligand-bound complexes. The Asinex antiviral database was screened using a recently resolved S protein (PDB ID: 7C2L). The Schrodinger software suite was used for preparing the protein and ligand structures prior to performing the docking experiment. Based on the docking scores, antiviral compounds were screened and the docked complexes of top-performing hits were tested for complex stability and presence of molecular interactions using MD simulations. Finally, based on the nature of molecular interactions,
Structures of the SARS-CoV-2 spike glycoprotein and applications for novel drug development
Frontiers in Pharmacology
COVID-19 caused by SARS-CoV-2 has raised a health crisis worldwide. The high morbidity and mortality associated with COVID-19 and the lack of effective drugs or vaccines for SARS-CoV-2 emphasize the urgent need for standard treatment and prophylaxis of COVID-19. The receptor-binding domain (RBD) of the glycosylated spike protein (S protein) is capable of binding to human angiotensin-converting enzyme 2 (hACE2) and initiating membrane fusion and virus entry. Hence, it is rational to inhibit the RBD activity of the S protein by blocking the RBD interaction with hACE2, which makes the glycosylated S protein a potential target for designing and developing antiviral agents. In this study, the molecular features of the S protein of SARS-CoV-2 are highlighted, such as the structures, functions, and interactions of the S protein and ACE2. Additionally, computational tools developed for the treatment of COVID-19 are provided, for example, algorithms, databases, and relevant programs. Finally...
Potential antiviral peptides targeting the SARS-CoV-2 spike protein
BMC Pharmacology and Toxicology
Background The coronavirus disease caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection became an international pandemic and created a public health crisis. The binding of the viral Spike glycoprotein to the human cell receptor angiotensin-converting enzyme 2 (ACE2) initiates viral infection. The development of efficient treatments to combat coronavirus disease is considered essential. Methods An in silico approach was employed to design amino acid peptide inhibitor against the receptor-binding domain (RBD) of the SARS-CoV-2 spike protein. The designed inhibitor (SARS-CoV-2 PEP 49) consists of amino acids with the α1 helix and the β4 - β5 sheets of ACE2. The PEP-FOLD3 web tool was used to create the 3D structures of the peptide amino acids. Analyzing the interaction between ACE2 and the RBD of the Spike protein for three protein data bank entries (6M0J, 7C8D, and 7A95) indicated that the interacting amino acids were contained inside two regions of ACE...
Journal of Biosciences
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 the 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 drug, Bisoxatin (DB09219), which is used for the treatment of constipation and preparation of the colon for surgical procedures. It binds nicely at the S-protein-ACE2 interface by making substantial p-p interactions with Tyr505 in the 'Site 1' hook region of RBD and hydrophilic interactions with Glu406, Ser494, and Thr500. Bisoxatin consistently binds to the protein throughout the 100 ns simulation. Taken together, we propose that the discovered molecule, Bisoxatin may be a promising repurposable drug molecule to develop new chemical libraries for inhibiting SARS-CoV-2 entry into the host.
Applied Microbiology: Theory ＆ Technology, 2021
Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-COV-2) is a causative agent of the potentially fatal coronavirus disease (COVID-19). Coronavirus targets the human respiratory system primarily. It can also infect the gastrointestinal, hepatic, and central nervous systems of humans, avians, bats, livestock, mice, and many other wild animals, as these are primary targets of the pathogen. This study aims to screen out the most potent inhibitor for SARS-CoV-2 (COVID-19) spike glycoproteins among the selected drugs, and computational tools have been utilized for this purpose. The selected drugs have been designed to explore their structural properties in this study by molecular orbital calculation. To inhibit the spike glycoproteins, the performance of these drugs was also examined by molecular docking calculation. In improving the performance of drugs, non-bond interactions play a significant role. To determine the chemical reactivity of all the medicines, HOMO and LUMO energy values were also calculated. The combined calculations exhibited that Ledipasvir among the selected drugs can be the most potent drug to treat SARS-CoV-2 compared to other medications.
ACE-2-derived Biomimetic Peptides for the Inhibition of Spike Protein of SARS-CoV-2
SARS-CoV-2, a novel coronavirus causing overwhelming death and infection worldwide, has emerged as a pandemic. Compared to its predecessor SARS-CoV, SARS-CoV-2 is more infective for being highly contagious and exhibiting tighter binding with host angiotensin-converting enzyme 2 (hACE-2). The entry of the virus into host cells is mediated by the interaction of its spike protein with hACE-2. Thus, a peptide that has a resemblance to hACE-2 but can overpower the spike protein-hACE-2 interaction will be a potential therapeutic to contain this virus. The non-interacting residues in the receptor-binding domain of hACE-2 have been mutated to generate a library of 136 new peptides. Out of this library, docking and virtual screening discover seven peptides that can exert a stronger interaction with the spike protein than hACE-2. A peptide derived from simultaneous mutation of all the non-interacting residues of hACE-2 yields two-fold stronger interaction than hACE-2 and thus turns out here t...
2020
COVID-19 has globally spread and has become a new pandemic, but there is still no effective drugs or vaccines to treat or prevent this disease. SARS-Cov-2 invades human cells through its spike proteins interacting with human ACE2 receptors. One strategy to prevent the virus from entering cells is the interruption of the viral spike protein interacting with ACE2. In such an emergent situation, drug repurposing is a promising method for rapid drug development. Here, we selected around 15000 molecular candidates including FDA-approved drugs from DrugBank and natural compounds from TCMSP to perform virtual screening for potential molecules that can target viral spike protein based on its crystal structure. In this article, we present the top 20 molecules with high binding affinity with spike protein, of which, digitoxin, a cardiac glycoside in DrugBank and bisindigotin in TCMSP, extracted from indigo naturalis and polygoni tinctorii foliu, have the highest docking scores. In addition, w...