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Antiviral drugs prioritization for COVID-19 management based on rational selection


Affiliations
1 Biochemical Sciences Division, CSIR-National Chemical Laboratory, Dr. Homi Bhabha Road, Pune 411 008, India; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad 201 002, India
2 Pandit Bhagwat Dayal Sharma Post Graduate Institute of Medical Sciences, Rohtak 124 001, India
3 INTOX Private Limited, Pune 412 115, India
 

The SARS-CoV-2 infection has resulted in COVID-19 pandemic worldwide. It has infected around 0.1 billion individuals and caused 2 million fatalities across the globe till mid-January 2021. Drug repurposing has been utilized as the most preferred therapeutic intervention for COVID-19 mitigation due to its necessity and feasibility. To prioritize therapeutic regime against COVID-19, we used 61 antiviral drugs and their combinations. Selected molecules were subjected to virtual screening against: (i) human angiotensin-converting enzyme 2 receptor binding domain (hACE-2) which serves as an anchor for virus attachment and entry, (ii) SARS-CoV-2 RNA dependent RNA polymerase (RdRp) responsible for viral RNA replication, and (iii) SARS-CoV-2 main protease (MPro) needed for viral polyprotein slab proteolytic processing. Based on docking score, pharmacodynamic and pharmacokinetic parameters, combinations of Daclatasvir, Elbasvir, Indinavir, Ledipasvir, Paritaprevir and Rilpivirine were analysed further. Our analysis suggested Sofosbuvir in combination with Ledipasvir and Daclatasvir as potential therapeutic agents for SARS-CoV-2. The combined score suggests that these combinations have superior antiSARS-CoV-2 potential than Remdesivir and other investigational drugs. The present work provides a rationale-based approach to select drugs with possible anti-SARS-CoV-2 activity for further clinical evaluation.

Keywords

Drug repurposing, hACE-2, main protease, RNA dependent RNA polymerase, SARS-CoV-2
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  • Antiviral drugs prioritization for COVID-19 management based on rational selection

Abstract Views: 341  |  PDF Views: 124

Authors

Rakesh S. Joshi
Biochemical Sciences Division, CSIR-National Chemical Laboratory, Dr. Homi Bhabha Road, Pune 411 008, India; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad 201 002, India
Ashok P. Giri
Biochemical Sciences Division, CSIR-National Chemical Laboratory, Dr. Homi Bhabha Road, Pune 411 008, India; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad 201 002, India
Mahesh J. Kulkarni
Biochemical Sciences Division, CSIR-National Chemical Laboratory, Dr. Homi Bhabha Road, Pune 411 008, India; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad 201 002, India
Mahesh Gupta
Pandit Bhagwat Dayal Sharma Post Graduate Institute of Medical Sciences, Rohtak 124 001, India
Savita Verma
Pandit Bhagwat Dayal Sharma Post Graduate Institute of Medical Sciences, Rohtak 124 001, India
Dhruva Chaudhry
Pandit Bhagwat Dayal Sharma Post Graduate Institute of Medical Sciences, Rohtak 124 001, India
Narendra Deshmukh
INTOX Private Limited, Pune 412 115, India
Anita Chugh
INTOX Private Limited, Pune 412 115, India

Abstract


The SARS-CoV-2 infection has resulted in COVID-19 pandemic worldwide. It has infected around 0.1 billion individuals and caused 2 million fatalities across the globe till mid-January 2021. Drug repurposing has been utilized as the most preferred therapeutic intervention for COVID-19 mitigation due to its necessity and feasibility. To prioritize therapeutic regime against COVID-19, we used 61 antiviral drugs and their combinations. Selected molecules were subjected to virtual screening against: (i) human angiotensin-converting enzyme 2 receptor binding domain (hACE-2) which serves as an anchor for virus attachment and entry, (ii) SARS-CoV-2 RNA dependent RNA polymerase (RdRp) responsible for viral RNA replication, and (iii) SARS-CoV-2 main protease (MPro) needed for viral polyprotein slab proteolytic processing. Based on docking score, pharmacodynamic and pharmacokinetic parameters, combinations of Daclatasvir, Elbasvir, Indinavir, Ledipasvir, Paritaprevir and Rilpivirine were analysed further. Our analysis suggested Sofosbuvir in combination with Ledipasvir and Daclatasvir as potential therapeutic agents for SARS-CoV-2. The combined score suggests that these combinations have superior antiSARS-CoV-2 potential than Remdesivir and other investigational drugs. The present work provides a rationale-based approach to select drugs with possible anti-SARS-CoV-2 activity for further clinical evaluation.

Keywords


Drug repurposing, hACE-2, main protease, RNA dependent RNA polymerase, SARS-CoV-2

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DOI: https://doi.org/10.18520/cs%2Fv120%2Fi9%2F1464-1470