Pharmacophore-based approaches in the rational repurposing technique for FDA approved drugs targeting SARS-CoV-2 M<sup>pro</sup>

Balaramnavar, Vishal M.; Ahmad, Khurshid; Ahmad, Irfan; Kamal, Mehnaz; Jawed, Talaha

doi:10.1039/d0ra06038k

Cited by 26 publications

(29 citation statements)

References 43 publications

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“…Figure 2 F presents the features developed in 6LU7 using MVD 6.0. This model was also authenticated using the previously reported model for M pro with well-defined training and a test set of compounds [ 9 ]. The RMSD value of 0.032882 Å indicated the robustness of the model for virtual screening experiments.…”

Section: Resultsmentioning

confidence: 99%

“…It is well documented that the M pro of SARS-CoV-2 is one of the most tempting drug targets, as viral maturation eventually depends mainly on the function of M pro [ 7 , 8 , 9 ]. The inhibition of M pro has been shown to obstruct viral replication in certain studies.…”

Section: Introductionmentioning

confidence: 99%

“…The inhibition of M pro has been shown to obstruct viral replication in certain studies. In several early and recent studies targeting M pro , numerous novel inhibitors have been produced against this enzyme—either novel compounds or existing drugs [ 9 ]. Blocking M pro ’s activity would therefore prevent viral replication and transcription.…”

Section: Introductionmentioning

confidence: 99%

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Receptor-Based Pharmacophore Modeling in the Search for Natural Products for COVID-19 Mpro

2021

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Considering the urgency of the COVID-19 pandemic, we developed a receptor-based pharmacophore model for identifying FDA-approved drugs and hits from natural products. The COVID-19 main protease (Mpro) was selected for the development of the pharmacophore model. The model consisted of a hydrogen bond acceptor, donor, and hydrophobic features. These features demonstrated good corroboration with a previously reported model that was used to validate the present model, showing an RMSD value of 0.32. The virtual screening was carried out using the ZINC database. A set of 208,000 hits was extracted and filtered using the ligand pharmacophore mapping, applying the lead-like properties. Lipinski’s filter and the fit value filter were used to minimize hits to the top 2000. Simultaneous docking was carried out for 200 hits for natural drugs belonging to the FDA-approved drug database. The top 28 hits from these experiments, with promising predicted pharmacodynamic and pharmacokinetic properties, are reported here. To optimize these hits as Mpro inhibitors and potential treatment options for COVID-19, bench work investigations are needed.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Receptor-Based Pharmacophore Modeling in the Search for Natural Products for COVID-19 Mpro

2021

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“…The protease is active as a homodimer, structured by the dimerization of two protomers designated as monomer A and monomer B, and the catalytic dyad in each protomer is defined by Cys145 and its residues (Zhang et al, 2020b). This has led to the development of multiple studies with experimental and computational approaches in search of possible inhibitors that can effectively block the activity of this protease (Balaramnavar et al, 2020;Dai et al, 2020;Gao et al, 2020;Jin et al, 2020a;Jin et al, 2020b;Ngo et al, 2020;Zhang et al, 2020b). Work with the 3C-like proteinase from SARS coronavirus revealed that the Cys145 residue is key at the active site of 3CLpro (Huang et al, 2004), this advance allowed the mentioned residue to be an attractive target for covalent ligands to bind acting as inhibitors of 3CL pro .…”

Section: Molecular Docking Analysismentioning

confidence: 99%

In Silico Study of Coumarins and Quinolines Derivatives as Potent Inhibitors of SARS-CoV-2 Main Protease

et al. 2021

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The pandemic that started in Wuhan (China) in 2019 has caused a large number of deaths, and infected people around the world due to the absence of effective therapy against coronavirus 2 of the severe acute respiratory syndrome (SARS-CoV-2). Viral maturation requires the activity of the main viral protease (Mpro), so its inhibition stops the progress of the disease. To evaluate possible inhibitors, a computational model of the SARS-CoV-2 enzyme Mpro was constructed in complex with 26 synthetic ligands derived from coumarins and quinolines. Analysis of simulations of molecular dynamics and molecular docking of the models show a high affinity for the enzyme (∆Ebinding between −5.1 and 7.1 kcal mol−1). The six compounds with the highest affinity show Kd between 6.26 × 10–6 and 17.2 × 10–6, with binding affinity between −20 and −25 kcal mol−1, with ligand efficiency less than 0.3 associated with possible inhibitory candidates. In addition to the high affinity of these compounds for SARS-CoV-2 Mpro, low toxicity is expected considering the Lipinski, Veber and Pfizer rules. Therefore, this novel study provides candidate inhibitors that would allow experimental studies which can lead to the development of new treatments for SARS-CoV-2.

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“…A recent virtual screening study on 2100 compounds from the CHEMBL database, ZINC database, and FDA-approved drugs and molecules under clinical trials followed by subsequent MD-simulation studies have shown that Cobicistat, Ritonavir, Lopinavir, and Darunavir would act as potent inhibitors of M pro [65] . Virtual screening and MD-studies have also identified other FDA-approved drugs [66] , [67] , [68] for the inhibition of M pro . However, in vivo studies of these ligands can only yield their true efficacy against M pro .…”

Section: Drug Targets Of the Main Protease (M Promentioning

confidence: 99%

Drug targets, mechanisms of drug action, and therapeutics against SARS-CoV-2

Jena¹

2021

Chemical Physics Impact

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Pharmacophore-based approaches in the rational repurposing technique for FDA approved drugs targeting SARS-CoV-2 M^pro

Abstract: Novel coronavirus (CoV) is the primary etiological virus responsible for the pandemic that started in Wuhan in 2019–2020.

Cited by 26 publications

References 43 publications

Receptor-Based Pharmacophore Modeling in the Search for Natural Products for COVID-19 Mpro

Receptor-Based Pharmacophore Modeling in the Search for Natural Products for COVID-19 Mpro

In Silico Study of Coumarins and Quinolines Derivatives as Potent Inhibitors of SARS-CoV-2 Main Protease

Drug targets, mechanisms of drug action, and therapeutics against SARS-CoV-2

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Pharmacophore-based approaches in the rational repurposing technique for FDA approved drugs targeting SARS-CoV-2 Mpro

Abstract: Novel coronavirus (CoV) is the primary etiological virus responsible for the pandemic that started in Wuhan in 2019–2020.

Cited by 26 publications

References 43 publications

Receptor-Based Pharmacophore Modeling in the Search for Natural Products for COVID-19 Mpro

Receptor-Based Pharmacophore Modeling in the Search for Natural Products for COVID-19 Mpro

In Silico Study of Coumarins and Quinolines Derivatives as Potent Inhibitors of SARS-CoV-2 Main Protease

Drug targets, mechanisms of drug action, and therapeutics against SARS-CoV-2

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Pharmacophore-based approaches in the rational repurposing technique for FDA approved drugs targeting SARS-CoV-2 M^pro