Rationale Based Selection and Prioritization of Antiviral Drugs for COVID-19 Management

Rakesh Joshi, Ashok P. Giri, Mahesh J. Kulkarni, Mahesh Gupta, Savita Verma, Dhruva Chaudhary, Narendra Deshmukh, Anita Chugh

10.26434/chemrxiv.12429629.v1

Research curated

Abstract

Infection with SARS-CoV-2 has resulted in COVID-19 pandemic and infected more than 5 million individuals with around 0.35 million deaths worldwide till May 2020 end. Several efforts are on in search of therapeutic interventions, but the preferred way is drug repurposing due to the feasibility and urgency of the situation. To select and prioritize approved antiviral drugs and drug combinations for COVID-19, 61 antiviral drugs having proven safety profile in humans were subjected to virtual screening for binding to three select targets namely human angiotensin-converting enzyme receptor-2 receptor-binding domain (hACE-2) involved in virus entry, SARS-CoV-2 RNA dependent RNA polymerase (RdRp) responsible for viral RNA replication and SARS-CoV-2 main protease (MPro) causing proteolytic processing of viral polyprotein slab. Targeting multiple ‘disease pathogenesis specific proteins’ within a close network of interaction or having dependent functionality can provide effective intervention. Ledipasvir, Daclatasvir, Elbasvir, Paritaprevir, Rilpivirine and Indinavir were identified as candidate drugs of interest for COVID-19 based on a derived combined activity score, pharmacokinetic and pharmacodynamic parameters. Ledipasvir and Daclatasvir and their approved marketed combination with Sofosbuvir emerged as leading candidate drugs/drug combinations for SARS-CoV-2. These candidates have the potential for the antiviral activity for SARS-CoV-2 infection better than the investigational drug Remdesivir and other antiviral drugs/drug combinations being evaluated. These drugs/combinations merit systematic fast track preclinical and clinical evaluation for COVID- 19 management. The present work brings back attention to the potential usefulness of approved antiviral drugs/drug combinations, commonly available with established safety profile, currently not in focus for COVID-19. It provides a rationale based approach for the selection of drugs with potential antiviral activity against SARS-CoV-2 highlighting the desired properties.

Source: ChemRxiv

Related molecules

Name	Synonyms	Genes
RNA dependent RNA polymerase	RDR, viral RNA polymerase, RdRp, nsp12	rep, ORF1a-1b, RdRp
3C-like protease	3CLpro, Mpro, SARS coronavirus main peptidase, 3CLpro-SARS-CoV-2	rep, ORF1a-1b
Paritaprevir	Veruprevir
Daclatasvir
Rilpivirine
Elbasvir
Indinavir
Ledipasvir

Related interactions

Target	Drug	Type	Result
RNA dependent RNA polymerase	Ledipasvir	Computational	positive
3C-like protease	Ledipasvir	Computational	positive
RNA dependent RNA polymerase	Elbasvir	Computational	positive
3C-like protease	Elbasvir	Computational	positive
RNA dependent RNA polymerase	Paritaprevir	Computational	positive
3C-like protease	Paritaprevir	Computational	positive
RNA dependent RNA polymerase	Rilpivirine	Computational	positive
3C-like protease	Indinavir	Computational	negative
RNA dependent RNA polymerase	Indinavir	Computational	positive
RNA dependent RNA polymerase	Daclatasvir	Computational	positive
3C-like protease	Daclatasvir	Computational	positive
3C-like protease	Rilpivirine	Computational	positive