scholarly journals Pharmacoinformatics and Molecular Dynamic Simulation Studies Reveal Potential Inhibitors of SARS-CoV-2 Main Protease 3CLpro

2020 ◽  
Author(s):  
Mubarak A. Alamri ◽  
Muhammad Tahir ul Qamar ◽  
Safar M. Alqahtani
Keyword(s):  
Molecular Dynamic ◽  
Protease Inhibitors ◽  
Md Simulation ◽  
Simulation Studies ◽  
Simulation Approach ◽  
Main Protease ◽  
Essential Enzyme ◽  
Potential Inhibitors ◽  
Further Development ◽  
Catalytic Dyad

The SARS-CoV-2 was confirmed to cause the regional outbreak of coronavirus disease 2019 (COVID-19) in Wuhan, China. The 3C-like protease (3CLpro), an essential enzyme for viral replication, is a valid target to compacts SARS-CoV and MERS-CoV. In this research, an integrated library consisting of 1000 compounds from Asinex Focused Covalent (AFCL) library and 16 FDA-approved protease inhibitors were screened against SARS-CoV-2 3CLpro. Top compounds with significant docking scores and making stable interactions with catalytic dyad residues were obtained. The screening results in identification of compound 621 from AFCL library as well as Paritaprevir and Simeprevir from FDA-approved protease inhibitors as potential inhibitors of SARS-CoV-2 3CLpro. The mechanism and dynamic stability of binding between the identified compounds and SARS-CoV-2 3CLpro were characterized using 50 nanoseconds (ns) molecular dynamic (MD) simulation approach. The identified compounds are potential inhibitors worthy of further development as SARS-CoV-2 3CLpro inhibitors/drugs. Importantly, the identified FDA-approved therapeutics could be ready for clinical trials to treat infected patients and help to curb the COVID-19.

scholarly journals Gymnema Sylvestre A- Potential Inhibitor of COVID-19 Main Protease by MD Simulation Study

2020 ◽  
Author(s):  
Senthil Kumar Subramani ◽  
Yash Gupta ◽  
Manish Manish ◽  
GBKS Prasad
Keyword(s):  
Md Simulation ◽  
Docking Study ◽  
Binding Pocket ◽  
Gymnema Sylvestre ◽  
Molecular Docking Study ◽  
Main Protease ◽  
Strong Candidate ◽  
The Stability ◽  
Potential Inhibitors ◽  
Domain I

Gymnema sylvestre (GS) is one of the herbal plant used since in ancient times. The present study aimed to assess bioactive compounds GS mainly gymnemic acids as potential inhibitors for COVID-19 against Mpro enzyme using a molecular docking study. The docking score observed between -53.4 to - 42.4 of all gymnemic acids and its derivatives. Molecular Dynamics (MD) simulation studies carried out at 100ns supported the stability of GS molecules within the binding pocket. RMSD score of less than 3.6. mainly, our results supported that these GS molecules bind to the domain I & II, and domain II-III linker of 3CLpro enzyme, suggesting its suitability as strong candidate for therapeutic against COVID-19. <br>

scholarly journals In Silico Screening of Naturally Occurring Coumarin Derivatives for the Inhibition of the Main Protease of SARS-CoV-2

2020 ◽  
Author(s):  
Sona Lyndem ◽  
Sharat Sarmah ◽  
Sourav Das ◽  
Atanu Singha Roy
Keyword(s):  
Active Site ◽  
Preliminary Screening ◽  
Naturally Occurring ◽  
Main Protease ◽  
Coumarin Compounds ◽  
Potential Inhibitors ◽  
Novel Drug ◽  
Catalytic Dyad

<p>The dissemination of a novel corona virus, SARS-CoV-2, through rapid human to human transmission has led to a global health emergency. The lack of a vaccine or medication for effective treatment of this disease has made it imperative for developing novel drug discovery approaches. Repurposing of drugs is one such method currently being used to tackle the viral infection. The genome of SARS-CoV-2 replicates due to the functioning of a main protease called M<sup>pro</sup>. By targeting the active site of M<sup>pro</sup> with potential inhibitors, this could prevent viral replication from taking place. Blind docking technique was used to investigate the interactions between 29 naturally occurring coumarin compounds and SARS-CoV-2 main protease, M<sup>pro</sup>, out of which 17 coumarin compounds were seen to bind to the active site through the interaction with the catalytic dyad, His41 and Cys145, along with other neighbouring residues. On comparing the ΔG values of the coumarins bound to the active site of M<sup>pro</sup>, corymbocoumarin belonging to the class pyranocoumarins, methylgalbanate belonging to the class simple coumarins and heraclenol belonging to the class furanocoumarins, displayed best binding efficiency and could be considered as potential M<sup>pro</sup> protease inhibitors. Preliminary screening of these naturally occurring coumarin compounds as potential SARS-CoV-2 replication inhibitors acts as a stepping stone for further <i>in vitro</i> and <i>in vivo</i> experimental investigation and analytical validation. </p>

scholarly journals Extensive Crystallographic Fragment-Based Approach to Design SARS CoV2 3CLpro Main Protease Inhibitors and Related Metadata

2021 ◽  
Author(s):  
Sarfraz Ahmad ◽  
Iskandar Abdullah ◽  
Yean Kee Lee ◽  
Mamoona Nazir ◽  
Muhammad Usman Mirza ◽  
...  
Keyword(s):  
Small Molecules ◽  
Md Simulation ◽  
Data Bank ◽  
Binding Pocket ◽  
New Drugs ◽  
Main Protease ◽  
Binding Data ◽  
Starting Point ◽  
Bona Fide ◽  
Further Development

<p>3CLpro is a vital protein for the SARS-CoV-2 replications and its inhibition using small molecules is a <i>bona fide</i> approach used to develop new drugs against the virus. In this study, a comprehensive crystallography-guided fragment-based drug discovery approach was employed to design new inhibitors for SARS-CoV-2 3CLpro. Protein Data Bank was explored to find small molecules cocrystallized with SARS-CoV-2 3CLpro. The fragments sitting in the binding pocket (87) were interactively coupled using various linkers with the intention to get molecules having the same orientation as those of the constituting fragments. In total, 1251 couples were prepared and converted to maximum possible stereoisomers using LigPrep for screening using Glide (standard precision and extra precision), AutoDock Vina, and Prime MMGBSA. Top 22 hits having conformations similar to their cocrystallized fragments were selected for MD simulation on Desmond. MD simulation suggested that 15 hits had conformations very close to their constituting fragments. Results indicated that these hits were computationally reliable and could be considered for further development. This suggests that the study could provide a benchmark starting point for the further design of SARS-CoV-2 3CLpro inhibitors with improved binding (data provided). <br></p>

scholarly journals In silico discovery of SARS-CoV-2 main protease inhibitors from the carboline and quinoline database

2021 ◽  
Author(s):  
Eldar Muhtar ◽  
Mengyang Wang ◽  
Haimei Zhu
Keyword(s):  
Molecular Dynamics ◽  
Molecular Mechanics ◽  
Protease Inhibitors ◽  
Surface Area ◽  
In Silico ◽  
Binding Energies ◽  
Main Protease ◽  
Poisson Boltzmann ◽  
Dynamics Simulations ◽  
Potential Inhibitors

Aim: SARS-CoV-2 caused more than 3.8 million deaths according to the WHO. In this urgent circumstance, we aimed at screening out potential inhibitors targeting the main protease of SARS-CoV-2. Materials & methods: An in-house carboline and quinoline database including carboline, quinoline and their derivatives was established. A virtual screening in carboline and quinoline database, 50 ns molecular dynamics simulations and molecular mechanics Poisson−Boltzmann surface area calculations were carried out. Results: The top 12 molecules were screened out preliminarily. The molecular mechanics Poisson−Boltzmann surface area ranking showed that p59_7m, p12_7e, p59_7k stood out with the lowest binding energies of -24.20, -17.98, -17.67 kcal/mol, respectively. Conclusion: The study provides powerful in silico results that indicate the selected molecules are valuable for further evaluation as SARS-CoV-2 main protease inhibitors.

scholarly journals Potential bioactive glycosylated flavonoids as SARS-CoV-2 main protease inhibitors: A molecular docking and simulation studies

PLoS ONE ◽  
2020 ◽  
Vol 15 (10) ◽  
pp. e0240653 ◽  
Author(s):  
Sabri Ahmed Cherrak ◽  
Hafida Merzouk ◽  
Nassima Mokhtari-Soulimane
Keyword(s):  
Molecular Docking ◽  
Protease Inhibitors ◽  
Simulation Studies ◽  
Main Protease
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