Selective Targeting of SARS-CoV-2 Spike Protein by Isatin-HydrazideHybrids: Synergistic In vitro and Molecular Dynamics Approaches

Abstract

INTRODUCTION: SARS-CoV-2 has significantly impacted people's lives worldwide. The viral genome has undergone numerous unanticipated changes that have led to the creation of new varieties and raised concerns across the globe. As the bioactive phytochemicals from both natural and synthetic origins have become a promising therapeutic approach due to their high ability to suppress pathogenic viruses. METHODS: The current work reports 9 novel isatin hydrazide conjugates as inhibitors of the SARSCoV- 2 spike protein, using in vitro and in silico approaches. RESULTS: It's interesting to note that, except for compounds 3a, 3e, and 3h all the remaining compounds showed significant to high inhibition, with inhibitory values ranging from 91.50 to 77.40 %. Here, compounds 3b (86.80 %), 3c (89.30 %), 3d (81.60 %), 3f (87.30 %), 3g (84.40 %), 3i (91.50 %), and compound 3l (85.49 %) resulted in high inhibitory potential. While 3j compound with 77.40 % inhibition significantly inhibited the SARS-CoV-2 spike protein. With docking scores ranging from -7.1 to -9.1 kcal/mol, the molecular docking of these compounds showed an excellent fit of molecules in the spike protein receptor binding domain (RBD) with good interactions with the RBD's essential residues. Additionally, a 100 ns molecular dynamics simulation showed that the complexes 3i-6M0J and Narlaprevir-6M0J were highly stable. DISCUSSION: This study highlights the prospective therapeutic potential of new isatin hydrazide conjugates for the treatment of COVID-19 by identifying them as strong SARS-CoV-2 spike protein inhibitors that have been confirmed by docking and molecular dynamics. CONCLUSION: The results of these in vitro and in silico experiments suggest their medical potential in treating SARS-CoV-2 infection with high potency. Therefore, these tiny compounds have the potential to be therapeutic agents.