Inspired by the initial reports of natural compounds showing promising results against M Pro , we designed a computational strategy for the detailed investigation of quinazoline pharmacophore against the main protease of SARS_CoV_2. Purposefully, we constructed an adequate library of 41 natural quinazoline alkaloids (Figure ) from two natural product databases, COCONUT and NPBS , for a full-scale investigation. The initial screening of 41 compounds against our target M Pro was a necessary task and achieved by blending rigid molecular docking and pharmacokinetic analysis (Figure ). In brief, the entire library of compounds along with reference famotidine was subjected to grid-based rigid docking by Autodock4.2 using blind docking protocol where the entire protein was selected in grid mapping covering all possible binding sites. It was observed that all the alkaloids bind at the substrate binding cavity of the main protease and interact with the loop crucial for the enzymatic mechanism of the target . Comparing the binding energy and inhibition constant found from docking studies, we observed that alkaloids having an aromatic moeity at C3 of tetrahydropyrrole ring and at C6 of quinazoline frame displayed better result. For the screening purpose, the alkaloids were ranked according to their negative binding energy as obtained from the rigid docking as shown in Table . An initial cut-off was employed and nine compounds were selected having negative binding energy ≥ 9.8 Kcal/mol for the second screening based on pharmacokinetic analysis. These nine compounds were further evaluated for their pharmacokinetic and toxicity features using SwissADME server , pkCSM-pharmacokinetics server , and BIOVIA Discovery Studio ADMET predictors . The ADME properties of the compounds were measured on SwissADME based on Lipinski's rule (Supporting Table ), and were further checked using BIOVIA Discovery Studio ADMET predictors (Supporting Figure ). Additionally, the possible toxicities of these compounds were estimated by pkCSM-pharmacokinetics tool. The molecular weight of all the quinazoline alkaloids ranges between 335.36 to 427.45 indicating the efficient absorption, transportation and diffusion in the body. Moreover, the TPSA values of the 9 alkaloids were found to be in the range between the 70 -90 Å 2 indicating good intestinal absorption and cell permeability. Overall, the initial screened alkaloids showed good bio-availabilities based on Lipinski's rule and toxicity prediction.