HOLANDA, Vanderlan Nogueira.; LIMA, Elton Marlon de Araújo.; SILVA, Welson Vicente da.; MAIA, Rafael Trindade.; MEDEIROS, Rafael de Lima.; GHOSH, Arabinda.; LIMA, Vera Lúcia de Menezes.; FIGUEIREDO, Regina Celia Bressan Queiroz de.
Abstract:
In this work we aimed to perform an in silico predictive screening, docking and molecular dynamic
study to identify 1,2,3-triazole-phthalimide derivatives as drug candidates against SARS-CoV-2. The in
silico prediction of pharmacokinetic and toxicological properties of hundred one 1,2,3-triazole-phtalimide
derivatives, obtained from SciFinderVR library, were investigated. Compounds that did not show
good gastrointestinal absorption, violated the Lipinski’s rules, proved to be positive for the AMES test,
and showed to be hepatotoxic or immunotoxic in our ADMET analysis, were filtered out of our study.
The hit compounds were further subjected to molecular docking on SARS-CoV-2 target proteins. The
ADMET analysis revealed that 43 derivatives violated the Lipinski’s rules and 51 other compounds
showed to be positive for the toxicity test. Seven 1,2,3-triazole-phthalimide derivatives (A7, A8, B05,
E35, E38, E39, and E40) were selected for molecular docking and MFCC—ab initio analysis. The results
of molecular docking pointed the derivative E40 as a promising compound interacting with multiple
target proteins of SARS-CoV-2. The complex E40-Mpro was found to have minimum binding energy of
10.26 kcal/mol and a general energy balance, calculated by the quantum mechanical analysis, of
8.63 eV. MD simulation and MMGBSA calculations confirmed that the derivatives E38 and E40 have
high binding energies of 63.47 ± 3 and 63.31 ± 7 kcal/mol against SARS-CoV-2 main protease. In
addition, the derivative E40 exhibited excellent interaction values and inhibitory potential against SARCov-
2 main protease and viral nucleocapsid proteins, suggesting this derivative as a potent antiviral
for the treatment and/or prophylaxis of COVID-19.
