The isoquinoline derivative "CYNOVID" as a prospective anti-SARS-CoV-2 agent: An expanded investigative computational study
Amgad M. Rabie, Imane Yamari, Samir Chtita · European Journal of Medicinal Chemistry Reports · 2024
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.