Screening Malaria-box compounds to identify potential inhibitors against SARS-CoV-2 Mpro, using molecular docking and dynamics simulation studies

Ahamad, Shahzaib; Hema, Kanipakam; Birla, Shweta; Ali, Shaukat; Gupta, Dinesh

doi:10.1016/j.ejphar.2020.173664

Cited by 33 publications

(19 citation statements)

References 45 publications

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“…Studies focusing on the in silico design of potent drugs targeting SARS-CoV-2 M pro are increasing steadily; however, the clinical use of these desired drugs is questionable, corresponding to the possible limitations of passing clinical trials. Recently, a structural simulation study ( Ahamad et al, 2020 ) screened three malaria-box compounds (MB-241, MB-250, and Mb-266) as the best lead drugs binding on SARS-CoV-2 M pro ; however, whether these compounds have experimental and/or clinical inhibitory activities is unknown. The development of drugs with broad-spectrum antiviral activity is considered a long purposed goal in drug discovery ( Maurya et al, 2020 ).…”

Section: Discussion and Future Perspectivesmentioning

confidence: 99%

Structural Basis of Potential Inhibitors Targeting SARS-CoV-2 Main Protease

2021

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The Coronavirus disease-19 (COVID-19) pandemic is still devastating the world causing significant social, economic, and political chaos. Corresponding to the absence of globally approved antiviral drugs for treatment and vaccines for controlling the pandemic, the number of cases and/or mortalities are still rising. Current patient management relies on supportive treatment and the use of repurposed drugs as an indispensable option. Of a crucial role in the viral life cycle, ongoing studies are looking for potential inhibitors to the main protease (Mpro) of severe acute respiratory syndrome Coronavirus -2 (SARS-CoV-2) to tackle the pandemic. Although promising results have been achieved in searching for drugs inhibiting the Mpro, work remains to be done on designing structure-based improved drugs. This review discusses the structural basis of potential inhibitors targeting SARS-CoV-2 Mpro, identifies gaps, and provides future directions. Further, compounds with potential Mpro based antiviral activity are highlighted.

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Section: Discussion and Future Perspectivesmentioning

confidence: 99%

Structural Basis of Potential Inhibitors Targeting SARS-CoV-2 Main Protease

2021

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“…The run of 100 ns was performed and all the trajectories were recorded at every 4 ps for further validation. The calculations of RMSD, RMSF, SASA, Rg, intramolecular hydrogen bond, FEL and density distributions were analyzed 49,50 . The MD analysis, with the parameters mentioned above, was conducted using GROMACS toolsets.…”

Section: Methodsmentioning

confidence: 99%

“…The calculations of RMSD, RMSF, SASA, Rg, intramolecular hydrogen bond, FEL and density distributions were analyzed. 49,50 The MD analysis, with the parameters mentioned above, was conducted using GROMACS toolsets. The energy plots and graphs were marked and visualized using the QtGrace visualization tool.…”

Section: Simulationsmentioning

confidence: 99%

The structural, functional, and dynamic effect of Tau tubulin kinase1 upon a mutation: A neuro‐degenerative hotspot

Ahamad

Hema

Kumar

et al. 2021

J of Cellular Biochemistry

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Alzheimer's disease (AD) is a progressive disorder that causes brain cells to degenerate and die. AD is one of the common causes of dementia that leads to a decline in thinking, behavioral and social skills that disrupts a person's ability to function independently. Tau-tubulin kinase1 (TTBK1) is a crucial disease regulating AD protein, which is majorly responsible for the phosphorylation and accumulation of tau protein at specific Serine/Threonine residues found in paired helical filaments, suggesting its role in tauopathy.TTBK1 involvement in many diseases and the restricted expression of TTBK1 to the central nervous system (CNS) makes TTBK1 an attractive therapeutic target for tauopathies. The genetic variations in TTBK1 are primarily involved in the TTBK1 pathogenesis. This study highlighted the destabilizing, damaging and deleterious effect of the mutation R142Q on TTBK1 structure through computational predictions and molecular dynamics simulations. The protein deviation, fluctuations, conformational dynamics, solvent accessibility, hydrogen bonding, and the residue-residue mapping confirmed the mutant effect to cause structural aberrations, suggesting overall destabilization due to the protein mutation. The presence of well-defined free energy minima was observed in TTBK1-wild type, as opposed to that in the R142Q mutant, reflecting structural deterioration. The overall findings from the study reveal that the presence of R142Q mutation on TTBK1 is responsible for the structural instability, leading to disruption of its biological functions. The mutation could be used as future diagnostic markers in treating AD.

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“…Pmax(q) represents the probability of the most probable state. The protein movements and the dynamic motions of WT and L452R, E484Q, double mutant L452R-E484Q throughout the trajectories in the subspace were further identified by Cartesian coordinates projecting the most important eigenvectors from the complete analysis (Ahamad et al 2021b).…”

Section: Principal Component Analysis (Pca)mentioning

confidence: 99%

Insights into the structure and dynamics of SARS-CoV-2 spike glycoprotein double mutant L452R-E484Q

et al. 2022

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The Receptor Binding Domain (RBD) of SARS-CoV-2, located on the S1 subunit, plays a vital role in the virus binding and its entry into the host cell through angiotensin-converting enzyme 2 (ACE2) receptor. Therefore, understanding the dynamic effects of mutants on the SARS-CoV-2 RBD is essential for discovering drugs to inhibit the virus binding and disrupt its entry into the host cells. A recent study reported a double mutant of SARS-CoV-2, L452R-E484Q, located in the RBD region. Thus, this study employed various computational algorithms and methods to understand the structural impact of both individual variants L452R, E484Q, and the double mutant L452R-E484Q on the native RBD of spike glycoprotein. The effects of the mutations on native RBD structure were predicted by in silico algorithms, which predicted changes in the protein structure and function upon the mutations. Subsequently, molecular dynamics (MD) simulations were employed to understand the conformational stability and functional changes on the RBD upon the mutations. The comparative results of MD simulation parameters displayed that the double mutant induces significant conformational changes in the spike glycoprotein RBD, which may alter its biological functions.

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Screening Malaria-box compounds to identify potential inhibitors against SARS-CoV-2 Mpro, using molecular docking and dynamics simulation studies

Cited by 33 publications

References 45 publications

Structural Basis of Potential Inhibitors Targeting SARS-CoV-2 Main Protease

Structural Basis of Potential Inhibitors Targeting SARS-CoV-2 Main Protease

The structural, functional, and dynamic effect of Tau tubulin kinase1 upon a mutation: A neuro‐degenerative hotspot

Insights into the structure and dynamics of SARS-CoV-2 spike glycoprotein double mutant L452R-E484Q

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