Marine drugs as putative inhibitors against non-structural proteins of SARS-CoV-2: an in silico study

INTRODUCTION: Coronavirus disease 2019 (COVID-19) is an unprecedented pandemic, threatening human health worldwide. The need to produce novel small-molecule inhibitors against the ongoing pandemic has resulted in the use of drugs such as chloroquine, azithromycin, dexamethasone, favipiravir, ribavirin, remdesivir and azithromycin. Moreover, the reports of the clinical trials of these drugs proved to produce detrimental effects on patients with side effects like nephrotoxicity, retinopathy, cardiotoxicity and cardiomyopathy. Recognizing the need for effective and non-harmful therapeutic candidates to combat COVID-19, we aimed to develop promising drugs against SARS-COV-2. DISCUSSION: In the current investigation, high-throughput virtual screening was performed using the Comprehensive Marine Natural Products Database against five non-structural proteins: Nsp3, Nsp5, Nsp12, Nsp13 and Nsp15. Furthermore, standard precision (SP) docking, extra precision (XP) docking, binding free energy calculation and absorption, distribution, metabolism, excretion and toxicity studies were performed using the Schrӧdinger suite. The top-ranked 5 hits obtained by computational studies exhibited to possess a greater binding affinity with the selected non-structural proteins. Amongst the five hits, CMNPD5804, CMNPD20924 and CMNPD1598 hits were utilized to design a novel molecule (D) that has the capability of interacting with all the key residues in the pocket of the selected non-structural proteins. Furthermore, 200 ns of molecular dynamics simulation studies provided insight into the binding modes of D within the catalytic pocket of selected proteins. CONCLUSION: Hence, it is concluded that compound D could be a promising inhibitor against these non-structural proteins. Nevertheless, there is still a need to conduct in vitro and in vivo studies to support our findings. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s00894-023-05574-9.