In silico study to identify novel potential thiadiazole-based molecules as anti-Covid-19 candidates by hierarchical virtual screening and molecular dynamics simulations.

UNLABELLED

In the present study, a new category of 1,3,4-thiadiazoles was developed by submitting methyl 2-(4-hydroxy-3-methoxybenzylidene) hydrazine-1-carbodithioate to react with the appropriate hydrazonoyl halides in presence of few drops of diisopropyl ethyl amine. The chemical structures of the newly synthesized derivatives were inferred by means of their micro-analytical and spectral data. Utilizing combined molecular docking and molecular dynamics techniques, the binding affinities and features of the synthesized compounds were evaluated against four SARS-CoV-2 target enzymes, namely, main protease (M), papain-like protease (PL), RNA-dependent RNA polymerase (RdRp), and receptor-binding domain (RBD) of the spike protein. Compound demonstrated promising binding affinities with the target enzymes M, PL, RdRp, and RBD with docking scores of -11.4, -9.4, -8.2, and -6.8 kcal/mol, respectively. In addition, compound exhibited MM-GBSA//100 ns MD docking score of -35.9 kcal/mol against M. Structural and energetic analyses revealed the stability of the -M complex over 100 ns MD simulations. In addition, compound obeyed Lipinski's rule of five, as it has acceptable absorption, distribution, and oral bioavailability inside the body. Therefore, compound is considered as a promising starting point for designing potential therapeutic agents against Covid-19.

SUPPLEMENTARY INFORMATION

The online version contains supplementary material available at 10.1007/s11224-022-01985-1.