Identification of 1,2,3-triazole-phthalimide derivatives as potential drugs against COVID-19: a virtual screening, docking and molecular dynamic study

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 similar to 10.26 kcal/mol and a general energy balance, calculated by the quantum mechanical analysis, of similar to 8.63 eV. MD simulation and MMGBSA calculations confirmed that the derivatives E38 and E40 have high binding energies of similar to 63.47 +/- 3 and similar to 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.

Automated summary

This study aimed to identify 1,2,3-triazole-phthalimide derivatives as potential drug candidates against SARS-CoV-2 through in silico screening, docking, and molecular dynamics. Among 101 derivatives investigated, compounds with poor pharmacokinetic properties or toxicity were filtered out, and seven selected compounds showed promising interactions with multiple target proteins of SARS-CoV-2, indicating their potential as antiviral agents for COVID-19 treatment or prevention.