Design and In-silico Screening of Peptide Nucleic Acid (PNA) Inspired Novel Pronucleotide Scaffolds Targeting COVID-19
Copyright© Bentham Science Publishers; For any queries, please email at epubbenthamscience.net..
INTRODUCTION: The outburst of the novel coronavirus COVID-19, at the end of December 2019 has turned into a pandemic, risking many human lives. The causal agent being SARS-CoV-2, a member of the long-known Coronaviridae family, is a positive-sense single-stranded enveloped virus and closely related to SARS-CoV. It has become the need of the hour to understand the pathophysiology of this disease, so that drugs, vaccines, treatment regimens and plausible therapeutic agents can be produced.
METHODS: In this regard, recent studies uncovered the fact that the viral genome of SARS-CoV-2 encodes non-structural proteins like RNA-dependent RNA polymerase (RdRp) which is an important tool for its transcription and replication process. A large number of nucleic acid-based anti-viral drugs are being repurposed for treating COVID-19 targeting RdRp. Few of them are at the advanced stage of clinical trials, including remdesivir. While performing a detailed investigation of the large set of nucleic acid-based drugs, we were surprised to find that the synthetic nucleic acid backbone has been explored very little or rare.
RESULTS: We designed scaffolds derived from peptide nucleic acid (PNA) and subjected them to in- -silico screening systematically. These designed molecules have demonstrated excellent binding towards RdRp. Compound 12 was found to possess a similar binding affinity as remdesivir with comparable pharmacokinetics. However, the in-silico toxicity prediction indicates that compound 12 may be a superior molecule which can be explored further due to its excellent safety-profile with LD50 12,000mg/kg as opposed to remdesivir (LD50 =1000mg/kg).
CONCLUSION: Compound 12 falls in the safe category of class 6. Synthetic feasibility, equipotent binding and very low toxicity of this peptide nucleic acid-derived compound can make it a leading scaffold to design, synthesize and evaluate many similar compounds for the treatment of COVID-19.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2022 |
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| Erschienen: |
2022 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:18 |
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| Enthalten in: |
Current computer-aided drug design - 18(2022), 1 vom: 20., Seite 26-40 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Sahu, Bichismita [VerfasserIn] |
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| Links: |
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| Anmerkungen: |
Date Completed 21.01.2022 Date Revised 21.01.2022 published: Print Citation Status MEDLINE |
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| doi: |
10.2174/1573409916666200923143935 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| 500 | |a published: Print | ||
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| 520 | |a Copyright© Bentham Science Publishers; For any queries, please email at epubbenthamscience.net. | ||
| 520 | |a INTRODUCTION: The outburst of the novel coronavirus COVID-19, at the end of December 2019 has turned into a pandemic, risking many human lives. The causal agent being SARS-CoV-2, a member of the long-known Coronaviridae family, is a positive-sense single-stranded enveloped virus and closely related to SARS-CoV. It has become the need of the hour to understand the pathophysiology of this disease, so that drugs, vaccines, treatment regimens and plausible therapeutic agents can be produced | ||
| 520 | |a METHODS: In this regard, recent studies uncovered the fact that the viral genome of SARS-CoV-2 encodes non-structural proteins like RNA-dependent RNA polymerase (RdRp) which is an important tool for its transcription and replication process. A large number of nucleic acid-based anti-viral drugs are being repurposed for treating COVID-19 targeting RdRp. Few of them are at the advanced stage of clinical trials, including remdesivir. While performing a detailed investigation of the large set of nucleic acid-based drugs, we were surprised to find that the synthetic nucleic acid backbone has been explored very little or rare | ||
| 520 | |a RESULTS: We designed scaffolds derived from peptide nucleic acid (PNA) and subjected them to in- -silico screening systematically. These designed molecules have demonstrated excellent binding towards RdRp. Compound 12 was found to possess a similar binding affinity as remdesivir with comparable pharmacokinetics. However, the in-silico toxicity prediction indicates that compound 12 may be a superior molecule which can be explored further due to its excellent safety-profile with LD50 12,000mg/kg as opposed to remdesivir (LD50 =1000mg/kg) | ||
| 520 | |a CONCLUSION: Compound 12 falls in the safe category of class 6. Synthetic feasibility, equipotent binding and very low toxicity of this peptide nucleic acid-derived compound can make it a leading scaffold to design, synthesize and evaluate many similar compounds for the treatment of COVID-19 | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Covid-19 | |
| 650 | 4 | |a In-silico screening | |
| 650 | 4 | |a RNA dependent-RNA polymerase | |
| 650 | 4 | |a peptide nucleic acid | |
| 650 | 4 | |a pronucleotides | |
| 650 | 4 | |a remdesivir analogues. | |
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| 700 | 1 | |a Behera, Santosh Kumar |e verfasserin |4 aut | |
| 700 | 1 | |a Das, Rudradip |e verfasserin |4 aut | |
| 700 | 1 | |a Dalvi, Tanay |e verfasserin |4 aut | |
| 700 | 1 | |a Chowdhury, Arnab |e verfasserin |4 aut | |
| 700 | 1 | |a Dewangan, Bhaskar |e verfasserin |4 aut | |
| 700 | 1 | |a Kalia, Kiran |e verfasserin |4 aut | |
| 700 | 1 | |a Shard, Amit |e verfasserin |4 aut | |
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