The coloring area of the surface represents the overall molecular charge distribution with the electrostatic potential. As for the compounds in this study, the electronegative potential (MESP min ) was coded with red on the MESP maps in a range from 202.16 to 152.27 kcal/mol indicating a strongest attraction while the interpolated blue map represents the electropositive potential (MESP max ) of a strongest repulsion varying from 15.68 to 42.67 kcal/mol. The predominance of green region in the MESP surfaces corresponds to a potential halfway between the two extremes that are indicated in red and blue colors, respectively. MESP plotted onto constant electron density surface for most active compound 1 showed the most electronegative potential region (red color) over the oxygen atom of the carbonyl group near the piperazine moiety. However, in the case of the least active compound 20, most negative potentials due to sulfonyl and carbonyl oxygen atoms are missing. For hit compounds, appearance of localized negative potential regions located at the oxygen atoms of the carbonyl and sulfonyl groups and nitrogen of the pyridine ring are consistent with the docking results which recognized this region as hydrogen bond acceptor. Moreover, one more prominent localized negative charged region protruding over the oxadiazole group was oriented adjacent to Gly193, to be recognized as a hydrogen bond acceptor. The strong electrostatic interaction of the negative potential with key residues Gly193 and Ser195, namely the formation of the hydrogen bond, will enhance the inhibition effect substantially together with the orbital interaction through the exchange of energy. The blue electropositive maps of these compounds were mainly distributed over the methyl group. The hydrogen atoms attached to the six-membered rings also bear the maximum brunt of positive charge (blue region). Due to the accumulation of positive potential, these moieties exhibited π···π and π···σ interactions with the aromatic residues of active site. These molecular electrostatic potential features are also in concert with the key chemical features (HBA and HY-AR) of pharmacophore model (Hypo1) which was successfully employed as a 3D structural query for virtual screening of databases for the identification of new potent chymase inhibitors. Thus electrostatic potential of the inhibitors can play a significant role in the binding and interaction with chymase together with orbital energies, and consequently influence the inhibition effect.