Fragment-based design of SARS-CoV-2 Mpro inhibitors

Teli, Divya M.; Patel, Bansari; Chhabria, Mahesh T.

doi:10.1007/s11224-022-02031-w

Cited by 10 publications

(3 citation statements)

References 36 publications

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“…In similar studies performed recently, Teli, Mahesh, Unival and Chhabria [168–171] presented fragment linkage strategy to design the new M pro enzyme inhibitors for COVID‐19 using computational chemistry software. The molecules were screened for their binding affinity with M pro , ADMET and Druglikeness properties, making them promising for the development of anti‐SARS‐Cov‐2 drugs.…”

Section: Resultsmentioning

confidence: 95%

Pharmacological Potential of Pyrmidine Derivatives: A Review With Emphasis on Antiviral Effects and Virtual Screening Against Sars‐Cov‐2 Molecular Targets

et al. 2023

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The importance of R&D of new antivirals has been highly evident with the emergence of the pandemic caused by SARS‐CoV‐2. Pyrimidines are heterocyclic compounds with a broad biological spectrum. In this review we emphasize the antiviral application of pyrimidines. Scientific articles, drug and patent registrations were searched using terms involving antiviral pyrimidines. Between 2012 and 2022, more than 100 articles, which show the broad antiviral spectrum of these compounds, were added in this review. The publications of the last five years were prioritized. Anti‐HIV applications were found, their use more evident within the framework of antivirals; among others found were anti‐influenza, anti‐arboviral, and anti‐hepatitis viruses. The results found in the drug and patent databases corroborate the scenario observed in the analysis of scientific articles and demonstrate the importance of researching pyrimidine compounds in periods of great impact on global health. Additionally, through virtual screening of 119 pyrimidines from an in‐house library, we found seventeen pyrimidines with high binding potential with the Mpro and RdRp proteins of SARS‐CoV‐2. Almost all seventeen compounds showed good pharmacokinetic and toxicological profile, mainly compounds 150 and 151 being considered promising for biological evaluation against SARS‐CoV‐2.

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Section: Resultsmentioning

confidence: 95%

Pharmacological Potential of Pyrmidine Derivatives: A Review With Emphasis on Antiviral Effects and Virtual Screening Against Sars‐Cov‐2 Molecular Targets

et al. 2023

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“…We identi ed nearly 500 phytochemicals with docking scores above − 7.5 kcal/mol across ve protein conformations. The criteria for the docking score cutoff was based on the docking scores observed for reported small-molecule M Pro inhibitors 35,36,37 . Our analysis revealed a preference for the binding site within Cluster 3, as approximately 200 compounds bound to this conformation with scores above the set threshold.…”

Section: Molecular Dockingmentioning

confidence: 99%

Unlocking the potential of phytochemicals in inhibiting SARS-CoV-2 M Pro protein - An in-silico and cell-based approach

Singh,

Patten,

Dimet

et al. 2024

Preprint

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The main protease (MPro) of SARS-CoV-2 plays a crucial role in viral replication and is a prime target for therapeutic interventions. Phytochemicals, known for their antiviral properties, have been previously identified as potential MPro inhibitors in several in silico studies. However, the efficacy of these remains in question owing to the inherent flexibility of the MPro binding site, posing challenges in selecting suitable protein structures for virtual screening. In this study, we conducted an extensive analysis of the MPro binding pocket, utilizing molecular dynamics (MD) simulations to explore its conformational diversity. Based on pocket volume and shape-based clustering, five representative protein conformations were selected for virtual screening. Virtual screening of a library of ~ 48,000 phytochemicals suggested 39 phytochemicals as potential MPro inhibitors. Based on subsequent MM-GBSA binding energy calculations and ADMET property predictions, five compounds were advanced to cell-based viral replication inhibition assays, with three compounds (demethoxycurcumin, shikonin, and withaferin A) exhibiting significant (EC50 < 10 uM) inhibition of SARS-CoV-2 replication. Our study provides an understanding of the binding interactions between these phytochemicals and MPro, contributing significantly to the identification of promising MPro inhibitors. Furthermore, beyond its impact on therapeutic development against SARS-CoV-2, this research highlights a crucial role of proper nutrition in the fight against viral infections.

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“…As the SARS-CoV-2 mutation rate is high, therapy becomes challenging. Some antiviral agents, such as remdesivir, paxlovid (nirmatrelvir/ritonavir), and molnupiravir, are authorized for the management of COVID-19 [ 21 , 22 ]. The WHO also recommends the emergency use of COVID-19 vaccines such as Covishield (Serum Institute of India Pvt.…”

Section: Introductionmentioning

confidence: 99%

Molnupiravir: A Versatile Prodrug against SARS-CoV-2 Variants

et al. 2023

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The nucleoside analog β-D-N4-hydroxycytidine is the active metabolite of the prodrug molnupiravir and is accepted as an efficient drug against COVID-19. Molnupiravir targets the RNA-dependent RNA polymerase (RdRp) enzyme, which is responsible for replicating the viral genome during the replication process of certain types of viruses. It works by disrupting the normal function of the RdRp enzyme, causing it to make mistakes during the replication of the viral genome. These mistakes can prevent the viral RNA from being transcribed, converted into a complementary DNA template, translated, or converted into a functional protein. By disrupting these crucial steps in the viral replication process, molnupiravir can effectively inhibit the replication of the virus and reduce its ability to cause disease. This review article sheds light on the impact of molnupiravir and its metabolite on SARS-CoV-2 variants of concern, such as delta, omicron, and hybrid/recombinant variants. The detailed mechanism and molecular interactions using molecular docking and dynamics have also been covered. The safety and tolerability of molnupiravir in patients with comorbidities have also been emphasized.

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Fragment-based design of SARS-CoV-2 Mpro inhibitors

Cited by 10 publications

References 36 publications

Pharmacological Potential of Pyrmidine Derivatives: A Review With Emphasis on Antiviral Effects and Virtual Screening Against Sars‐Cov‐2 Molecular Targets

Pharmacological Potential of Pyrmidine Derivatives: A Review With Emphasis on Antiviral Effects and Virtual Screening Against Sars‐Cov‐2 Molecular Targets

Unlocking the potential of phytochemicals in inhibiting SARS-CoV-2 M Pro protein - An in-silico and cell-based approach

Molnupiravir: A Versatile Prodrug against SARS-CoV-2 Variants

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