The isoquinoline derivative "CYNOVID" as a prospective anti-SARS-CoV-2 agent: An expanded investigative computational study

Abstract

Isoquinoline compounds holding some nucleosidic structural hallmarks are considered possible attractive options for effectively combating the different severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections and their associated disease, the coronavirus disease 2019 (COVID-19). The CYNOVID molecule ((S)-6-chloro-2-{[(1-cyanocyclopropyl)methyl]sulfonyl}-N-(isoquinolin-4-yl)-1,2,3,4-tetrahydroisoquinoline-4-carboxamide) is a recently-discovered isoquinoline compound with potent anticoronaviral activities against several SARS-CoV-2 variants according to different antiviral cellular assays. CYNOVID nonspecifically binds to the main protease (M^pro) enzyme of several coronaviruses. As an extensive continued effort to develop this potential anti-SARS-CoV-2 agent and examine its nonspecific broad potential to be an effective broad-spectrum anti-COVID-19 therapy, a new comprehensive in-silico research study was proposed and designed to explore the inhibitory abilities of this isoquinoline derivative against the two major highly-conserved SARS-CoV-2 replication enzymes (i.e., the SARS-CoV-2 replication proteins other than M^pro), which are the RNA-dependent RNA polymerase (RdRp) and 3′-to-5′ exoribonuclease (ExoN) enzymes. The various computational results of the present study significantly supported the previous biochemical/biological findings as well as the newly-suggested multiple-targeting hypothesis, disclosing the possible nonspecific anticoronaviral activities of this promising experimental agent, CYNOVID, against nearly any coronaviral-2 variants and, probably, any future coronaviral species, e.g., SARS-CoV-3.