DFT based calculation was carried out for our selected hits CNP0416047, 3-hydroxy anisotine, anisotine and for reference famotidine in order to examine the electron distribution on the frontier molecular orbitals and to calculate the HOMO-LUMO band gaps. The HOMO-LUMO energy gap has been linked to reactivity of a molecule and extrapolated to the activity of the bound inhibitor inside the enzyme catalytic cavity . The calculations were carried out using two different methods, B3LYP/6-311+G(D,P) (Table ) and w-B97XD/6-311+G(D,P) (Supporting Table ), and the independent findings of both calculations supported each other. As shown in Table , the HOMO-LUMO bandgaps of CNP0416047, 3-hydroxy anisotine and anisotine are comparable to the band gap of reference famotidine predicting that HOMO of inhibitor may smoothly transfer the electrons to the LUMO while interacting with amino acid residues at M Pro binding site. Moreover, the electron distribution at the frontier molecular orbital diagram of the hits corroborated with the findings from docking studies (Figure ). The HOMO-LUMO structures of both 3-hydroxy anisotine and anisotine displayed high electron density at the aromatic moiety attached to 3-position of tetrahydropyrrole ring showing that these aromatic moieties can exhibit strong interaction with protein residues, which supported the screening results as the alkaloids having similar structures exhibited better interaction profiles in rigid docking. Additionally, the HOMO structure of CNP0416047 has electrons localized on quinazoline frame whereas the LUMO structure has electrons on tyrosine moiety attached to C6 of quinazoline ring. From the HOMO and LUMO structures, it can be concluded that the quinazoline frame of CNP0416047 is available to donate electron to the interacting residues of the protein and in agreement with the docking results as explained in previous section. The electron distribution at the frontier molecular orbital of the hits CNP0416047, 3-hydroxy anisotine, anisotine and for reference famotidine as calculated by B3LYP/6-311+G(D,P) method.