Using integrated computational approaches to identify safe and rapid treatment for SARS-CoV-2

Al-Khafaji, Khattab; AL-Duhaidahawi, Dunya; Tok, Tuğba Taşkın

doi:10.1080/07391102.2020.1764392

Cited by 120 publications

(101 citation statements)

References 37 publications

(37 reference statements)

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“…Most of the published studies making use of MD simulations evaluate the stability of the initial binding poses through the analysis of: (i) the RMSD of both the 3CLpro and the drug, (ii) the root-mean-square fluctuation (RMSF), and (iii) the radius of gyration ( R g ). These three descriptors are essential in evaluating the pose stability, as the RMSD determines the structural stability, the RMSF reveals the drug effect on the system flexibility and fluctuations, and R g is indicative of the compactness of the global structure (refs ( 143 , 173 , 175 , 184 , 185 , 187 , 188 , 190 , and 200 )). In addition, more specific criteria, such as the development of particular hydrogen bonds and hydrophobic interactions, are crucial to discriminate between potential or not efficient drugs because they ultimately determine the position of the drug with respect to the 3CLpro.…”

Section: Sars-cov-2 Proteasesmentioning

confidence: 99%

Molecular Basis of SARS-CoV-2 Infection and Rational Design of Potential Antiviral Agents: Modeling and Simulation Approaches

et al. 2020

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The emergence in late 2019 of the coronavirus SARS-CoV-2 has resulted in the breakthrough of the COVID-19 pandemic that is presently affecting a growing number of countries. The development of the pandemic has also prompted an unprecedented effort of the scientific community to understand the molecular bases of the virus infection and to propose rational drug design strategies able to alleviate the serious COVID-19 morbidity. In this context, a strong synergy between the structural biophysics and molecular modeling and simulation communities has emerged, resolving at the atomistic level the crucial protein apparatus of the virus and revealing the dynamic aspects of key viral processes. In this Review, we focus on how in silico studies have contributed to the understanding of the SARS-CoV-2 infection mechanism and the proposal of novel and original agents to inhibit the viral key functioning. This Review deals with the SARS-CoV-2 spike protein, including the mode of action that this structural protein uses to entry human cells, as well as with nonstructural viral proteins, focusing the attention on the most studied proteases and also proposing alternative mechanisms involving some of its domains, such as the SARS unique domain. We demonstrate that molecular modeling and simulation represent an effective approach to gather information on key biological processes and thus guide rational molecular design strategies.

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Section: Sars-cov-2 Proteasesmentioning

confidence: 99%

Molecular Basis of SARS-CoV-2 Infection and Rational Design of Potential Antiviral Agents: Modeling and Simulation Approaches

et al. 2020

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“…Another co-crystal (PDB-ID 6Y2F/6Y2G), a-ketoamide inhibitor (13b) is also reported recently, providing the structural and residue-based architecture of catalytic sites . These co-crystals are paving the route for the application of virtual screening (VS) to get more efficacious molecules (Al-Khafaji et al, 2020;Kumar et al, 2020;Lobo-Galo et al, 2020).…”

Section: Introductionmentioning

confidence: 99%

Identification of potential molecules against COVID-19 main protease through structure-guided virtual screening approach

Mittal

Kumari

Srivastava

et al. 2020

Journal of Biomolecular Structure and Dynamics

165

106

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The pandemic caused by novel coronavirus disease 2019 infecting millions of populations worldwide and counting, has demanded quick and potential therapeutic strategies. Current approved drugs or molecules under clinical trials can be a good pool for repurposing through in-silico techniques to quickly identify promising drug candidates. The structural information of recently released crystal structures of main protease (M pro ) in APO and complex with inhibitors, N3, and 13b molecules was utilized to explore the binding site architecture through Molecular dynamics (MD) simulations. The stable state of M pro was used to conduct extensive virtual screening of the aforementioned drug pool. Considering the recent success of HIV protease molecules, we also used anti-protease molecules for drug repurposing purposes. The identified top hits were further evaluated through MD simulations followed by the binding free energy calculations using MM-GBSA. Interestingly, in our screening, several promising drugs stand out as potential inhibitors of M pro . However, based on control (N3 and 13b), we have identified six potential molecules, Leupeptin Hemisulphate, Pepstatin A, Nelfinavir, Birinapant, Lypression and Octreotide which have shown the reasonably significant MM-GBSA score. Further insight shows that the molecules form stable interactions with hot-spot residues, that are mainly conserved and can be targeted for structure-and pharmacophore-based designing. The pharmacokinetic annotations and therapeutic importance have suggested that these molecules possess drug-like properties and pave their way for in-vitro studies. ARTICLE HISTORY

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“…Therefore, this drug is a potential candidate to inhibit the FP and RBM sites of the spike glycoprotein. It has also been reported by computational methods effect on 3C-like protease (3CL pro) also called the main protease (Mpro) [1,11], so it could be considered a multi-target drug, which confers a greater probability of success.…”

Section: Discussionmentioning

confidence: 99%

Repositioning of ligands that target spike glycoprotein as potential drugs against SARS-CoV-2

Ramírez-Salinas¹,

Martínez‐Archundia²,

Correa-Basurto³

et al. 2020

Preprint

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The worldwide health emergency of the SARS-CoV-2 pandemic and the absence of a specific treatment for this new coronavirus have led to the use of computational strategies (drug repositioning) to search for treatments. The aim of this work is to identify FDA-approved drugs with the potential for binding to the spike structural glycoprotein at the hinge site, receptor binding motif (RBM), and fusion peptide (FP) using molecular docking simulations. It was identified drugs that binding to amino acids crucial for down to up conformational change, receptor recognition, and fusion of the viral membrane with the cell membrane. Results show some drugs that bind to hinge site amino acids (Varenicline, or even steroids as Betamethasone) while other drugs bind to crucial amino acids for RBM (Naldemedine, Atovaquone, Cefotetan) or FP (Edarbi, Maraviroc, Difluprednate); and highlights the Saquinavir that binds both the RBM and the FP. Therefore, these drugs could inhibit spike glycoprotein and prevent viral entry (possible anti-COVID-19 drugs). Several drugs are in clinical studies; focused on another pharmacological target (candesartan, Atovaquone, Losartan, Maviroc and Ritonavir) in this work we propose an additional target, the spike glycoprotein. These results can impact in the proposal of treatments that can inhibit the first steps virus replication cycle.

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Using integrated computational approaches to identify safe and rapid treatment for SARS-CoV-2

Cited by 120 publications

References 37 publications

Molecular Basis of SARS-CoV-2 Infection and Rational Design of Potential Antiviral Agents: Modeling and Simulation Approaches

Molecular Basis of SARS-CoV-2 Infection and Rational Design of Potential Antiviral Agents: Modeling and Simulation Approaches

Identification of potential molecules against COVID-19 main protease through structure-guided virtual screening approach

Repositioning of ligands that target spike glycoprotein as potential drugs against SARS-CoV-2

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