In this study, we have done a detailed computational investigation on natural quinazoline alkaloids by constructing an adequate library of 41 samples from two natural product databases in the search for potential inhibitors of the main protease (M pro ) of SARS_CoV_2. After two rounds of screenings based on rigid docking, flexible docking and ADMET profiling, we identified three quinazoline alkaloids as promising hit compounds. Furthermore, the stereo-electronic features of hit alkaloids were further investigated through additional structure-based E-pharmacophore mapping and DFT based calculations. Finally, the stabilities of complexes between hit alkaloids with the protein were accessed extensively using robust molecular dynamics simulation through RMSD, RMSF, Rg, and MM-PBSA calculation.