scholarly journals Crystal-Structures-Guided Design of Fragment-Based Drugs for Inhibiting the Main Protease of SARS-CoV-2

2020 ◽  
Author(s):  
Binquan Luan ◽  
Tien Huynh
Keyword(s):  
Binding Free Energy ◽  
Dynamics Simulation ◽  
Drug Molecule ◽  
Protein Targets ◽  
Main Protease ◽  
Potent Drug ◽  
Approved Drugs ◽  
Fda Approved Drugs ◽  
Efficacious Drug ◽  
Better Than

Abstract Since the beginning of the COVID-19 pandemic, researchers and scientists across the globe are racing to find a cure for the highly contagious infectious disease caused by the SARS-CoV-2 virus. Despite many promising ongoing progress, there are currently no FDA approved drugs to treat infected patients. Among the various protein targets of SARS-CoV-2 virus, the main protease (Mpro) has attracted most interests. Recently, the crowdsourcing of drug discovery for inhibiting Mpro have yielded a plenty of drug fragments resolved inside the active site of Mpro via the crystallography method. Following the principle of fragment-based drug design (FBDD), we are motivated to design a potent drug molecule through merging several of these newly discovered drug fragments. Among various designed ligands, we found that B19 by merging three fragments JFM, U0P and HWH is the most stable one, evidenced through extensive (~10 μs totally) all-atom molecular dynamics simulation. We further estimated that the binding free energy of B19 is comparable or even a little better than that of a native protein ligand processed by Mpro. Our promising results suggest that B19 can potentially be an efficacious drug molecule for inhibiting Mpro of SARS-CoV-2.

scholarly journals Identification of 3-chymotrypsin like protease (3CLPro) inhibitors as potential anti-SARS-CoV-2 agents

2021 ◽  
Vol 4 (1) ◽  
Author(s):  
Vicky Mody ◽  
Joanna Ho ◽  
Savannah Wills ◽  
Ahmed Mawri ◽  
Latasha Lawson ◽  
...  
Keyword(s):  
Inhibitory Effect ◽  
Dynamics Simulation ◽  
Simulation Studies ◽  
Inhibitory Effects ◽  
Major Threat ◽  
Main Protease ◽  
Approved Drugs ◽  
Fda Approved Drugs ◽  
Computational Molecular Modeling

AbstractEmerging outbreak of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection is a major threat to public health. The morbidity is increasing due to lack of SARS-CoV-2 specific drugs. Herein, we have identified potential drugs that target the 3-chymotrypsin like protease (3CLpro), the main protease that is pivotal for the replication of SARS-CoV-2. Computational molecular modeling was used to screen 3987 FDA approved drugs, and 47 drugs were selected to study their inhibitory effects on SARS-CoV-2 specific 3CLpro enzyme in vitro. Our results indicate that boceprevir, ombitasvir, paritaprevir, tipranavir, ivermectin, and micafungin exhibited inhibitory effect towards 3CLpro enzymatic activity. The 100 ns molecular dynamics simulation studies showed that ivermectin may require homodimeric form of 3CLpro enzyme for its inhibitory activity. In summary, these molecules could be useful to develop highly specific therapeutically viable drugs to inhibit the SARS-CoV-2 replication either alone or in combination with drugs specific for other SARS-CoV-2 viral targets.

scholarly journals Screening of FDA Approved Drugs Against COVID-19 Main Protease: Coronavirus Disease

2020 ◽  
Author(s):  
Vijayakumar Balakrishnan ◽  
Karthik Lakshminarayanan
Keyword(s):  
Vaccine Development ◽  
New Drugs ◽  
World Health ◽  
Wuhan City ◽  
Drug Candidates ◽  
Human Contact ◽  
Main Protease ◽  
Potent Drug ◽  
Approved Drugs ◽  
Fda Approved Drugs

In the end of December 2019, a new strain of coronavirus was identified in the Wuhan city of Hubei province in China. Within a shorter period of time, an unprecedented outbreak of this strain was witnessed over the entire Wuhan city. This novel coronavirus strain was later officially renamed as COVID-19 (Coronavirus disease 2019) by the World Health Organization. The mode of transmission had been found to be human-to-human contact and hence resulted in a rapid surge across the globe where more than 1,100,000 people have been infected with COVID-19. In the current scenario, finding potent drug candidates for the treatment of COVID-19 has emerged as the most challenging task for clinicians and researchers worldwide. Identification of new drugs and vaccine development may take from a few months to years based on the clinical trial processes. To overcome the several limitations involved in identifying and bringing out potent drug candidates for treating COVID-19, in the present study attempts were made to screen the FDA approved drugs using High Throughput Virtual Screening (HTVS). The COVID-19 main protease (COVID-19 Mpro) was chosen as the drug target for which the FDA approved drugs were initially screened with HTVS. The drug candidates that exhibited favorable docking score, energy and emodel calculations were further taken for performing Induced Fit Docking (IFD) using Schrodinger’s GLIDE. From the flexible docking results, the following four FDA approved drugs Sincalide, Pentagastrin, Ritonavir and Phytonadione were identified. In particular, Sincalide and Pentagastrin can be considered potential key players for the treatment of COVID-19 disease.

scholarly journals Repurposing of FDA-approved Drugs against Active Site and Potential Allosteric Drug Binding Sites of COVID-19 Main Protease

2021 ◽  
Author(s):  
Merve Yuce ◽  
Erdem Cicek ◽  
Tuğçe İnan ◽  
Aslıhan Başak Dağ ◽  
Özge Kürkçüoğlu ◽  
...  
Keyword(s):  
Active Site ◽  
Social Life ◽  
Binding Free Energy ◽  
Antiviral Drug ◽  
Drug Binding ◽  
Allosteric Site ◽  
Main Protease ◽  
Allosteric Sites ◽  
Approved Drugs ◽  
Fda Approved Drugs

The novel coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) still has serious negative effects on health, social life, and economics. Recently, vaccines from various companies have been urgently approved to control SARS-CoV-2 infections. However, any specific antiviral drug has not been confirmed so far for regular treatment. An important target is the main protease (Mpro), which plays a major role in replication of the virus. In this study, Gaussian and residue network models are employed to reveal two distinct potential allosteric sites on Mpro that can be evaluated as drug targets besides the active site. Then, FDA-approved drugs are docked to three distinct sites with flexible docking using AutoDock Vina to identify potential drug candidates. 14 best molecule hits for the active site of Mpro are determined. 6 of these also exhibit high docking scores for the potential allosteric regions. Full-atom molecular dynamics simulations with MM-GBSA method indicate that compounds docked to active and potential allosteric sites form stable interactions with high binding free energy (∆Gbind) values. ∆Gbind values reach -52.06 kcal/mol for the active site, -51.08 kcal/mol for the potential allosteric site 1, and -42.93 kcal/mol for the potential allosteric site 2. Energy decomposition calculations per residue elucidate key binding residues stabilizing the ligands that can further serve to design pharmacophores. This systematic and efficient computational analysis successfully determines ivermectine, diosmin and selinexor currently subjected to clinical trials, and further proposes bromocriptine, elbasvir as Mpro inhibitor candidates to be evaluated against SARS-CoV-2 infection

scholarly journals Targeting the SARS-CoV-2 main protease using FDA-approved Isavuconazonium, a P2-P3 α-ketoamide derivative and Pentagastrin: an in-silico drug discovery approach

2020 ◽  
Author(s):  
Ikechukwu Achilonu ◽  
Emmanuel Amarachi Iwuchukwu ◽  
Okechinyere Juliet Achilonu ◽  
Manuel Antonio Fernandes
Keyword(s):  
Computational Study ◽  
Conformational Dynamics ◽  
Dynamics Simulation ◽  
Ligand Docking ◽  
Salt Bridges ◽  
Main Protease ◽  
Approved Drugs ◽  
Fda Approved Drugs ◽  
Docking Energy ◽  
Site Binding

Abstract The SARS-CoV-2 main protease (Mpro) is an attractive target towards discovery of drugs to treat COVID-19 because of its key role in virus replication. The atomic structure of Mpro in complex with an α-ketoamide inhibitor (Lig13b) is available (PDB ID:6Y2G). Using 6Y2G and the prior knowledge that protease inhibitors could eradicate COVID-19, we designed a computational study aimed at identifying FDA-approved drugs that could interact with Mpro. We searched the DrugBank and PubChem for analogs and built a virtual library containing ~33000 conformers. Using high-throughput virtual screening and ligand docking, we identified Isavuconazonium, a ketoamide inhibitor (α-KI) and Pentagastrin as the top three molecules (Lig13b as the benchmark) based on docking energy. The ΔGbind of Lig13b, Isavuconazonium, α-KI, Pentagastrin was -117.68, -191.11, -187.36, -145.76 kJ/mol, respectively. Molecular dynamics simulation revealed that these ligands are stable within the Mpro active site. Binding of these ligands is driven by a variety of non-bonded interaction, including polar bonds, H-bonds, van der Waals and salt bridges. The overall conformational dynamics of the complexed-Mpro was slightly altered relative to apo-Mpro. This study demonstrates that three distinct classes molecules, Isavuconazonium (triazole), α-KI (ketoamide) and Pentagastrin (peptide) could serve as potential drugs to treat patients with COVID-19.

scholarly journals Interactions mechanism of commonly used drugs for the treatment of Covid-19

2021 ◽  
Vol 34 (3) ◽  
pp. 613-623
Author(s):  
S. Celik ◽  
A. D. Demirag ◽  
A. E. Ozel ◽  
S. Akyuz
Keyword(s):  
Binding Free Energy ◽  
Autodock Vina ◽  
Spike Glycoprotein ◽  
Docking Analysis ◽  
Drug Molecules ◽  
Protease Enzyme ◽  
Main Protease ◽  
Poisson Boltzmann ◽  
Approved Drugs ◽  
Fda Approved Drugs

In this study conformation analysis of seven drugs commonly used in the treatment of COVID-19 was performed. The most stable conformers of the drug molecules were used as initial data for docking analysis. Using the Cavityplus program, the probable most active binding sites of both apo and holo forms of COVID-19 main protease enzyme (Mpro) and spike glycoprotein of SARSCoV-2 receptors were determined. The interaction mechanisms of the 7 FDA approved drugs (arbidol, colchicine, dexamethasone, favipiravir, galidesivir, hydroxychloroquine, remdesivir) were examined using the AutoDock Vina program. The six of the seven drugs were found to be more stable in binding to apo form of COVID-19 Mpro and spike glycoprotein. Moreover, a set of molecular mechanics (MM) Poisson-Boltzmann (PB) surface area (SA) calculations on the investigated drugs-protein systems were performed and the estimated binding free energy of remdesivir and the apo form of Mpro system was found to be the best. The interaction results of FDA drugs with the apo form of COVID-19 Mpro and spike glycoprotein can play an important role for the treatment of COVID-19.                     KEY WORDS: COVID-19, Drugs, Molecular modelling, Conformational analysis, Molecular docking   Bull. Chem. Soc. Ethiop. 2020, 34(3), 613-623. DOI: https://dx.doi.org/10.4314/bcse.v34i3.16

Phenylbenzopyrone of flavonoids as a potential scaffold to prevent SARS-CoV-2 replication by inhibiting its MPRO main protease

2021 ◽  
Vol 22 ◽  
Author(s):  
Angamba Meetei Potshangbam ◽  
Potshangbam Nongdam ◽  
A. Kiran Kumar ◽  
R.S. Rathore
Keyword(s):  
Antiviral Drugs ◽  
Dynamics Simulation ◽  
Compound Libraries ◽  
Main Protease ◽  
Enterovirus A71 ◽  
Short Period ◽  
Novel Coronavirus ◽  
Effective Drugs ◽  
Drug Leads ◽  
Better Than

Background: In December 2019, an outbreak of a pneumonia-like illness, Coronavirusdisease-2019 (COVID-19), originating from Wuhan, China was linked to novel coronavirus, now termed SARS-CoV-2. Unfortunately, no effective drugs or vaccines have been reported yet. The main protease (MPRO) remains the most validated pharmacological target for the design and discovery of inhibitors. Objective: The purpose of the study was to find a prospective natural scaffold as an inhibitor for MPRO main protease in SARS-CoV-2 and compare it with repurposed antiviral drugs lopinavir and nelflinavir. Methods: Natural compound libraries were screened for potential scaffold against MPRO main protease. Molecular dynamics simulation, MM-GBSA and principle component analyses of enzyme-ligand complexes were carried out with the top-ranking hits and compared with the repurposed antiviral drugs lopinavir and nelfinavir. Results: The structure-based virtual screening indicated phenylbenzopyrone of flavonoids as one of the top-ranking scaffolds that have the potential to inhibit the main protease with O-glycosidic form performing better than corresponding aglyconic form. Simulation studies indicated that glycosidic form of flavonoid as more suitable inhibitor with compounds rutin, procyanidin B6, baicalin and galloylquercetin, demonstrating high affinity and stability, and rutin emerging as one of the best candidate compound. Interestingly, rutin was reported to have inhibitory activity against similar protease (3Cprotease of enterovirus A71) as well as implicated in lung fibrosis. Conclusion: The present study displaying flavonoids, possessing a potential scaffold for inhibiting main protease activity for all betacoronavirus is an attempt to provide new and safe drug leads within a reasonably short period.

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