Despite the global effort to recover from the COVID-19 pandemic through vaccine procurements and the development of new treatments, the unpredictable fluctuations of symptomatic cases due to the increase in COVID-19 variants still demand the discovery of additional efficacious antiviral drugs. Cyanobacteria generate a wide array of biologically active secondary metabolites, establishing the domain of cyanotherapeutics. However, the therapeutic applications of cyanobacteria against SARS-CoV-2 are yet to be explored. In this study, 56 cyanobacterial secondary metabolites were screened for in silico inhibitory potential against five main target sites of SARS-CoV-2 involved in viral attachment and replication mechanisms. Top-ranked ligands were then subjected to molecular dynamics (MD) simulation. Pharmacokinetic properties and toxicity predictions were also performed. Of the 56 secondary metabolites molecularly docked, compounds 1–7 showed favorable binding energy ranging from –8.0 to –11.2 kcal/mol against the spike’s ACE2 (angiotensin-converting enzyme 2) and GRP 78 (glucose-related protein 78) receptor-binding domains, 3CLPRO (3-chymotrypsin-like protease), PLPRO (papain-like protease), and RdRp (RNA-dependent RNA-polymerase). Three compounds – scytonemin (1), a bisindole alkaloid dimer; enterobactin (2), and agardhipeptin A (3) – exhibited the highest binding affinities with BEs ranging from –8.2 to –11.2 kcal/mol. Through MD simulations, scytonemin (1) complexed with the spike RBD, 3CLPRO, and RdRp, as well as enterobactin (2) complexed with PLPRO demonstrated dynamic stability. Among the three top-scoring lead compounds, scytonemin (1) exhibited drug-like and favorable ADME properties. Hence, the top-scoring compounds from cyanobacteria present as favorable drug prototypes for optimizationand in vitro testing against SARS-CoV-2.

The novel severe acute respiratory syndrome coronavirus (SARS-CoV-2) emerged in December 2019 leading to a global pandemic and lockdowns in different countries including the Philippines. There is an oral antiviral treatment, Paxlovid, produced by Pfizer that is currently authorized for emergency use to treat COVID-19. However, there is still a necessity to discover specific antiviral drugs due to increasing cases worldwide. In this study, 56 cyanobacterial secondary metabolites were virtually screened for in silico inhibitory prospects against five main targeted proteins of SARS-CoV-2 involved in viral attachment, viral replication, and host immunity modulation mechanisms. Pharmacokinetic properties and toxicity predictions were also performed. Of the fifty-six secondary metabolites molecularly docked, compounds 1–7 showed favorable binding energy ranging from -10.9 to -8.0 kcal/mol against the spike’s ACE2 (angiotensin-converting enzyme 2) and GRP 78 (glucose-related protein 78) receptor binding domains, 3CLPRO (3-chymotrypsin-like protease), PLPRO (papain-like protease), and RdRp (RNA-dependent RNA-polymerase). Three compounds, scytonemin (1) a bisindole alkaloid dimer, cryptophycin (5) a macrolactam, and tjipanazole A2 (6) an indole alkaloid glucoside exhibited highest the binding affinities with BE’s ranging from -10.4 to -8.6 kcal/mol. Top-ranked ligands 1–7 also demonstrated favorable pharmacokinetics with low toxicity risks.