A comprehensive SARS-CoV-2 genomic analysis identifies potential targets for drug repurposing

Anand, Nithishwer Mouroug; Liya, Devang Haresh; Pradhan, Arpit Kumar; Tayal, Nitish; Bansal, Abhinav; Donakonda, Sainitin; Jainarayanan, Ashwin Kumar

doi:10.1371/journal.pone.0248553

Cited by 23 publications

(18 citation statements)

References 43 publications

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“…The Root Mean Square Deviation (RMSD) and Root Mean Square fluctuations analysis is an important quantitative measure of the stability of the protein-ligand complex. A wide persistent fluctuation in RMSD and RMSF trajectory is an indicator of conformational changes in the protein/ligand system [ 45 ]. The result of this study revealed a stable system for Ekebrin D4, Silafluofen and ZINC16919139 ( Fig.…”

Section: Resultsmentioning

confidence: 99%

In silico identification and study of potential anti-mosquito juvenile hormone binding protein (MJHBP) compounds as candidates for dengue virus - Vector insecticides

Ononamadu

Abdalla

Ihegboro

et al. 2021

Biochemistry and Biophysics Reports

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Dengue has become a huge global health burden. It is currently recognized as the most rapidly spreading mosquito-borne viral disease. Yet, there are currently no licensed vaccines or specific therapeutics to manage the virus, thus, scaling up vector control approaches is important in controlling this viral spread. This study aimed to identify and study in silico , potential anti-mosquito compounds targeting Juvenile hormone (JH) mediated pathways via the Mosquito Juvenile Hormone Binding Protein (MJHBP). The study was implemented using series of computational methods. The query compounds included pyrethroids and those derived from ZINC and ANPDB databases using a simple pharmacophore model in Molecular Operating Environment (MOE). Molecular docking of selected compounds’ library was implemented in MOE. The resultant high-score compounds were further validated by molecular dynamics simulation via Maestro 12.3 module and the respective Prime/Molecular Mechanics Generalized Born Surface Area (Prime/MM-GBSA) binding energies computed. The study identified compounds-pyrethroids, natural and synthetic - with high docking energy scores (ranging from 10.91–12.34 kcal/mol). On further analysis of the high-ranking (in terms of docking scores) compounds using MD simulation, the compounds - Ekeberin D4, Maesanin, Silafluofen and ZINC16919139- revealed very low binding energies (−122.99, −72.91 -104.50 and,-74.94 kcal/mol respectively), fairly stable complex and interesting interaction with JH-binding site amino acid residues on MJHBP. Further studies can explore these compounds in vitro/in vivo in the search for more efficient mosquito vector control.

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Section: Resultsmentioning

confidence: 99%

In silico identification and study of potential anti-mosquito juvenile hormone binding protein (MJHBP) compounds as candidates for dengue virus - Vector insecticides

Ononamadu

Abdalla

Ihegboro

et al. 2021

Biochemistry and Biophysics Reports

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“…Additionally, Darifenacin is reported among the 25 hits in Table 1. The antimuscarinic agent Darifenacin was previously predicted to have inhibitory capacity against several conserved molecular targets of SARS-CoV-2 by using both docking and dynamics simulation programs [49]. Then by reviewing the safety profile of these 25 drugs in Medscape clinical reference, only 14 hits were selected for further consideration and analysis.…”

Section: Resultsmentioning

confidence: 99%

Computational Screening of FDA Approved Drugs from ZINC Database for Potential Inhibitors of Zika Virus NS2B/NS3 Protease: A Molecular Docking and Dynamics Simulation Study

Odhar

Ahjel

Odhar

2021

JPRI

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Zika virus is a mosquito borne pathogen with a single strand RNA genome. Human infection with this virus is usually asymptomatic, however outbreaks reported in both Pacific region and Latin America have been associated with increase in frequency of microcephaly in newborns and fetuses of infected mothers. Also, the incidence of Guillain-Barré syndrome had also increased among adults with Zika virus infection. Currently, neither vaccine nor antiviral drug has been developed against Zika virus. Structure based virtual screening can be employed, through drug repurposing strategy, to accelerate the identification of potential anti-Zika virus candidates. As such, virtual screening of approved drugs against Zika virus NS2B/NS3 protease can help to recognize new hits capable of hindering viral ability to replicate and evade immune system of the host. In this computational study, we have screened 1615 FDA approved drugs against NS2B/NS3 protease enzyme of Zika virus by using both molecular docking and dynamics simulation. Our virtual screening results indicate that the anti-muscarinic agent Darifenacin and the anti-diarrheal agent Loperamide may have a promising capacity to inhibit Zika virus NS2B/NS3 protease. According to molecular docking and dynamics simulation, these two approved drugs have good binding capacity to NS2B/NS3 as reported by docking energy of binding and MM-PBSA binding energy. In addition, both Darifenacin and Loperamide were able to maintain close proximity to protease crystal throughout simulation period. However, invitro evaluation of these two drugs against Zika virus NS2B/NS3 protease is required to confirm these computational results.

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“…The mutational frequency across the spike subunit is directly related to its infection and transmission rates. From our previous study, the spike subunit was characterized as unstable with higher number of mutations among all regions (30). Over the time period there have been multitudes of mutations in spike, some beneficial and some that had no or less effect on its binding with the ACE2 receptor.…”

Section: Discussionmentioning

confidence: 99%

Spike selection in SARS-CoV-2 variants across different geographical regions reveals unique signature patterns and differential stability with drug interaction

Liya

Anand

Jainarayanan

et al. 2022

Preprint

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The evolution of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus since its emergence in 2019 has yielded several new viral variants with varied infectivity, disease severity, and antigenicity. Although most mutations are expected to be relatively neutral, mutations at the Spike region of the genome has shown to have a major impact on the viral transmission and infection in humans. Therefore, it is crucial to survey the structures of spike protein across the global virus population to contextualize the rate of therapeutic success against these variants. In this study, high-frequency mutational variants from different geographic regions were pooled in order to study the structural evolution of the spike protein through drug docking and MD simulations. We investigated the mutational burden in the spike sub regions and have observed that the different variants harbour unique signature patterns in the spike sub regions, with certain domains being highly prone to mutations. Further, the MD simulations and docking study revealed that different variants show differential stability when docked for the same set of drug targets. This work sheds light on the mutational burden and the stability landscape of the spike protein across the variants from different geographical regions.

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A comprehensive SARS-CoV-2 genomic analysis identifies potential targets for drug repurposing

Cited by 23 publications

References 43 publications

In silico identification and study of potential anti-mosquito juvenile hormone binding protein (MJHBP) compounds as candidates for dengue virus - Vector insecticides

In silico identification and study of potential anti-mosquito juvenile hormone binding protein (MJHBP) compounds as candidates for dengue virus - Vector insecticides

Computational Screening of FDA Approved Drugs from ZINC Database for Potential Inhibitors of Zika Virus NS2B/NS3 Protease: A Molecular Docking and Dynamics Simulation Study

Spike selection in SARS-CoV-2 variants across different geographical regions reveals unique signature patterns and differential stability with drug interaction

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