The isoquinoline derivative "CYNOVID" as a prospective anti-SARS-CoV-2 agent: An expanded investigative computational study
Amgad M. Rabie, Imane Yamari, Samir Chtita
Abstract
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. Shortage of successful anticoronaviral drugs is still a very critical problem in medicinal chemistry. Highlights • CYNOVID is a newly-synthesized potential anti-SARS-CoV-2/anticoronaviral agent, acting mainly via inhibition of the M pro protein. • The current study interestingly disclosed the possible broad activities of this compound against the coronaviral enzymes RdRp and ExoN. • CYNOVID computationally blocks the catalytic pockets of the RdRp and ExoN proteins with strong and stable binding affinities of -8.5 and -8.7 Kcal/mol, respectively, which promisingly synergizes and complements the other principal anti-M pro (antireplicative) effect. • CYNOVID also shows favorable predicted drug-likeness, ADMET, and toxicity profiles. • In conclusion, CYNOVID can be considered a prospective effective anti-COVID-19 isoquinolinic agent with broad-spectrum anticoronaviral activities.