scholarly journals Structure-Guided Design of Potent Inhibitors of SARS-CoV-2 3CL Protease: Structural, Biochemical, and Cell-Based Studies

2021 ◽  
Author(s):  
Chamandi S. Dampalla ◽  
Athri D. Rathnayake ◽  
Krishani Dinali Perera ◽  
Abdul-Rahman M. Jesri ◽  
Harry Nhat Nguyen ◽  
...  
Keyword(s):  
3Cl Protease

In Silico Identification of a Potent Arsenic Based Approved Drug Darinaparsin against SARS-CoV-2: Inhibitor of RNA Dependent RNA polymerase (RdRp) and Essential Proteases

2020 ◽  
Vol 20 ◽  
Author(s):  
Trinath Chowdhury ◽  
Gourisankar Roymahapatra ◽  
Santi M. Mandal
Keyword(s):  
Rna Polymerase ◽  
Viral Entry ◽  
In Silico ◽  
Rna Dependent Rna Polymerase ◽  
Replication Complex ◽  
In Silico Study ◽  
Life Threatening ◽  
In Vivo Analysis ◽  
3Cl Protease

Background: COVID-19 is a life threatening novel corona viral infection to our civilization and spreading rapidly. Terrific efforts are generous by the researchers to search for a drug to control SARS-CoV-2. Methods: Here, a series of arsenical derivatives were optimized and analyzed with in silico study to search the inhibitor of RNA dependent RNA polymerase (RdRp), the major replication factor of SARS-CoV-2. All the optimized derivatives were blindly docked with RdRp of SARS-CoV-2 using iGEMDOCK v2.1. Results: Based on the lower idock score in the catalytic pocket of RdRp, darinaparsin (-82.52 kcal/mol) revealed most effective among them. Darinaparsin strongly binds with both Nsp9 replicase protein (-8.77 kcal/mol) and Nsp15 endoribonuclease (-8.3 kcal/mol) of SARS-CoV-2 as confirmed from the AutoDock analysis. During infection, the ssRNA of SARS-CoV2 is translated into large polyproteins forming viral replication complex by specific proteases like 3CL protease and papain protease. This is also another target to control the virus infection where darinaparsin also perform the inhibitory role to proteases of 3CL protease (-7.69 kcal/mol) and papain protease (-8.43 kcal/mol). Conclusion: In host cell, the furin protease serves as a gateway to the viral entry and darinaparsin docked with furin protease which revealed a strong binding affinity. Thus, screening of potential arsenic drugs would help in providing the fast invitro to in-vivo analysis towards development of therapeutics against SARS-CoV-2.

scholarly journals Identification of pyrogallol as a warhead in design of covalent inhibitors for the SARS-CoV-2 3CL protease

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Haixia Su ◽  
Sheng Yao ◽  
Wenfeng Zhao ◽  
Yumin Zhang ◽  
Jia Liu ◽  
...  
Keyword(s):  
Theoretical Calculations ◽  
Cysteine Proteinase ◽  
Covalent Binding ◽  
Food Sources ◽  
Binding Mechanism ◽  
Covalent Inhibitors ◽  
Catalytic Cysteine ◽  
3Cl Protease ◽  
Covalent Ligands ◽  
Covalent Inhibitor

AbstractThe ongoing pandemic of coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) urgently needs an effective cure. 3CL protease (3CLpro) is a highly conserved cysteine proteinase that is indispensable for coronavirus replication, providing an attractive target for developing broad-spectrum antiviral drugs. Here we describe the discovery of myricetin, a flavonoid found in many food sources, as a non-peptidomimetic and covalent inhibitor of the SARS-CoV-2 3CLpro. Crystal structures of the protease bound with myricetin and its derivatives unexpectedly revealed that the pyrogallol group worked as an electrophile to covalently modify the catalytic cysteine. Kinetic and selectivity characterization together with theoretical calculations comprehensively illustrated the covalent binding mechanism of myricetin with the protease and demonstrated that the pyrogallol can serve as an electrophile warhead. Structure-based optimization of myricetin led to the discovery of derivatives with good antiviral activity and the potential of oral administration. These results provide detailed mechanistic insights into the covalent mode of action by pyrogallol-containing natural products and a template for design of non-peptidomimetic covalent inhibitors against 3CLpros, highlighting the potential of pyrogallol as an alternative warhead in design of targeted covalent ligands.

scholarly journals Structural basis for the development of SARS 3CL protease inhibitors from a peptide mimic to an aza ‐decaline scaffold

Biopolymers ◽  
2016 ◽  
Vol 106 (4) ◽  
pp. 391-403 ◽  
Author(s):  
Kenta Teruya ◽  
Yasunao Hattori ◽  
Yasuhiro Shimamoto ◽  
Kazuya Kobayashi ◽  
Akira Sanjoh ◽  
...  
Keyword(s):  
Protease Inhibitors ◽  
Structural Basis ◽  
Peptide Mimic ◽  
3Cl Protease

Molecular Docking of Azithromycin, Ritonavir, Lopinavir, Oseltamivir, Ivermectin and Heparin Interacting with Coronavirus Disease 2019 Main and Severe Acute Respiratory Syndrome Coronavirus-2 3C-Like Proteases

2021 ◽  
Vol 21 (4) ◽  
pp. 2075-2089
Author(s):  
Tiago da Silva Arouche ◽  
Anderson Yuri Martins ◽  
Teodorico de Castro Ramalho ◽  
Raul Nunes Carvalho Júnior ◽  
Fabio Luiz Paranhos Costa ◽  
...  
Keyword(s):  
Life Cycle ◽  
Viral Life Cycle ◽  
Stable Complex ◽  
Viral Agent ◽  
Main Protease ◽  
Wide Range ◽  
Approved Drugs ◽  
Pharmacologically Active ◽  
3Cl Protease

In the current pandemic situation raised due to COVID-19, drug reuse is emerging as the first line of treatment. The viral agent that causes this highly contagious disease and the acute respiratory syndrome coronavirus (SARS-CoV) share high nucleotide similarity. Therefore, it is structurally expected that many existing viral targets are similar to the first SARS-CoV, probably being inhibited by the same compounds. Here, we selected two viral proteins based on their vital role in the viral life cycle: Structure of the main protease SARS-CoV-2 and the structural base of the SARS-CoV-2 protease 3CL, both supporting the entry of the virus into the human host. The approved drugs used were azithromycin, ritonavir, lopinavir, oseltamivir, ivermectin and heparin, which are emerging as promising agents in the fight against COVID-19. Our hypothesis behind molecular coupling studies is to determine the binding affinities of these drugs and to identify the main amino acid residues that play a fundamental role in their mechanism of action. Additional studies on a wide range of FDA-approved drugs, including a few more protein targets, molecular dynamics studies, in vitro and biological in vivo evaluation are needed to identify combination therapy targeted at various stages of the viral life cycle. In our experiment in silico, based mainly on the molecular coupling approach, we investigated six different types of pharmacologically active drugs, aiming at their potential application alone or in combination with the reuse of drugs. The ligands showed stable conformations when analyzing the affinity energy in both proteases: ivermectin forming a stable complex with the two proteases with values −8.727 kcal/mol for Main Protease and −9.784 kcal/mol for protease 3CL, Heparin with values of −7.647 kcal/mol for the Main protease and −7.737 kcal/mol for the 3CL protease. Both conform to the catalytic site of the proteases. Our studies can provide an insight into the possible interactions between ligands and receptors, through better conformation. The ligands ivermectin, heparin and ritonavir showed stable conformations. Our in-silica docking data shows that the drugs we have identified can bind to the binding compartment of both proteases, this strongly supports our hypothesis that the development of a single antiviral agent targeting Main protease, or 3CL protease, or an agent used in combination with other potential therapies, it could provide an effective line of defense against diseases associated with coronaviruses.

scholarly journals Approach Towards Drugs Repurposing: Docking Studies with Multiple Target Proteins Associated with SARS-CoV-2

2020 ◽  
Author(s):  
Shiwani Rana ◽  
Meghali Panwar ◽  
Kalyan Sundar Ghosh
Keyword(s):  
Viral Infections ◽  
Molecular Targets ◽  
Drug Repurposing ◽  
Docking Studies ◽  
Extreme Situation ◽  
Angiotensin Converting Enzyme 2 ◽  
Viral Proteases ◽  
Docking Tool ◽  
Free Energy Of Binding ◽  
3Cl Protease

<p>The current pandemic outbreak of COVID-19 due to viral infections by SARS-CoV-2 is now become associated with severe commotion on global healthcare and economy. In this extreme situation when vaccine or drugs against COVID-19 are not available, the only quick and feasible therapeutic alternative would be the drug repurposing approach. In the present work, <i>in silico</i> screening of some antiviral and antiprotozoal drugs using Autodock docking tool was performed. Two known antiviral drugs sorivudine and noricumazole B are predicted to bind to the active site of the viral proteases namely cysteine like protease or 3CL protease (3CLpro) and papain like protease (PLpro) respectively with a highly favorable free energy of binding. Further, the promising molecules were subjected for checking their activity on other molecular targets like spike protein S1, RNA dependent RNA polymerase (RdRp) and angiotensin converting enzyme 2 (ACE2) receptor. But the compounds were found not effective on rest other molecular targets. </p>

Computational Simulations on the Binding and Reactivity of a Nitrile Inhibitor of SARS-CoV-2 Main Protease

2021 ◽  
Author(s):  
Carlos A. Ramos-Guzmán ◽  
José Javier Ruiz-Pernía ◽  
Iñaki Tuñón
Keyword(s):  
Free Energy ◽  
Computational Analysis ◽  
Binding Mode ◽  
Free Energy Calculations ◽  
The Novel ◽  
Computational Simulations ◽  
Main Protease ◽  
3Cl Protease ◽  
Alchemical Free Energy ◽  
Alchemical Free Energy Calculations

We present a detailed computational analysis of the binding mode and reactivity of the novel oral inhibitor PF-07321332 developed against SARS-CoV-2 3CL protease. Alchemical free energy calculations suggest that positions...

Virtual Screening of Phyto Chemicals Against SARS-CoV-2 Targets

2021 ◽  
Vol 6 (3) ◽  
pp. 61-76
Author(s):  
Shahanas Naisam ◽  
Vidhya V. S. ◽  
Suvanish Kumar ◽  
Nidhin Sreekumar
Keyword(s):  
Dynamics Simulation ◽  
Spike Protein ◽  
Ligand Interaction ◽  
Docking Analysis ◽  
Drug Molecules ◽  
In Vivo Analysis ◽  
Protein Ligand Interaction ◽  
The Stability ◽  
3Cl Protease

The COVID-19 pandemic wave has recommenced and is spreading like wildfire across the globe. The well-reported antiviral potency of phyto compounds could offer potential drug molecules for the current predicament. The present study analyses the molecular interaction of selected phyto compounds and SARS-CoV-2 molecular target proteins, namely spike protein, RNA-dependent RNA polymerase, 3C-like proteases, and papain-like protease. Ten newly modeled ligands were also considered for the study. Molecular docking analysis was carried out independently using MOE, AutoDock Vina, Schrodinger-Glide, and the stability of protein-ligand interaction was validated through molecular dynamics simulation. Petunidin interacts with spike protein resulting in a good Gscore, binding energy, and H-bond interaction. Also, alions, letestuianin-A, (+)-pinitol show better interaction with RdRp, 3CL-protease, and papain-like protease, respectively. The presented work screens through 2314 ligands to yield top-ranked molecules which could be taken up to develop potential lead molecules via in-vivo analysis.

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