HOMO and LUMO sites are plotted onto the molecular surface of most active (1) and least active (20) compounds of the data set along with the two hit (BTB, HTS) compounds ( Figure 11 ). Most often, the heteroaromatic rings, which contain the heteroatoms such as nitrogen and oxygen, are the regions in all these compounds that can act as electron donors or acceptors to the active site of the chymase. Experimental study also deduced that introduction of heteroatoms to the inhibitor compound enhanced its stability in human plasma (20) . For instance, the placement of an ethoxy group in compound 2 instigated its stability. Electron donor rings can be identified as those with the greatest electron density from the HOMO. In the case of compound 1, HOMO is scattered over the 4-methylpiperazine moiety together with the carbonyl group and LUMO is spread over the region 2-hydroxyl-4-oxoazetidine containing heteroatoms like oxygen and nitrogen. Docking results also showed that this region of compound 1 is involved in important interactions with the key residues of protein. For compound 20, HOMO is composed of aniline ring and LUMO spreads over sulfonyl and benzoic acid groups. LUMO plot over methylbenzenesulfonamide group in hit compounds BTB showed hydrogen bonding interactions with important amino acids Gly193 and Ser195 at the active site of the enzyme. Whereas the HOMO plot is scattered on 2-methoxyphenol group and dihydroquinazolin moiety, the six membered ring part of dihydroquinazolin group is involved in important π···π interactions with the side chain imidazole ring of His57 amino acid. For HTS hit compound, HOMO and LUMO are composed of methoxybenzene, benzoindazole moieties, and oxadiazole substituted pyridine moiety, respectively. Overlay of HTS on "Hypo1" and its docking with the protein also speculated the involvement of these groups in key interactions with the active site of protein. The effect of the orbital energies on the inhibition activities can be associated with the charge transfer, π···π, or π···σ stacking between inhibitors and aromatic amino acid residues in the binding site of chymase. The result of molecular docking studies on chymase inhibitors also proved the presence of such kind of interactions.