The results show that the negative electrostatic potential is located mainly over the oxygen atoms, while a null to positive potential is spread along the remaining parts of the psoralen structure. The negative electrostatic potential is mainly located in two areas, one over the furan oxygen, and the other across the oxygen atoms of the coumarin moiety. Taking into account the molecular docking studies, these regions are the ones that interact more closely with the binding site of CYP2A6, namely the Asn297 and the iron from the heme cofactor. Depending on the groups that are located on the position 2 of the coumarin ring, other bulky negative potential areas exist (compounds 1, 3, 4 and 5). Depending on the conformational arrangement of these groups, it might occur a superimposition on the negative electrostatic potential promoted by the coumarin ring. This effect improves the nucleophilic characteristics of the psoralens in those regions and renders them more reactive. This effect is observed in compounds 1 and 3, for which the two negatively electrostatic regions are superimposed, due to the vicinity of an oxygen atom from the ethoxycarbonyl and from the carboxyl group of the lactone. It is important to notice that these two compounds are those that show the best antiproliferative effect against most of the cell lines studied. Together with the molecular docking, these results suggest that this effect might favor the interaction of compound 1 with the Asn297 that is important for ligand recognition, or in the case of compound 3 to promote the direct chelation of the substrate with the heme group of the CYP2A6. The same effect is however not observed in compounds 4 and 5, in which the formation of intramolecular hydrogen bonds or even by the steric hindrance caused by the bulky groups precludes this effect. As a consequence, the most stable conformations for these compounds present these regions pointing towards the opposite direction of the other two common negative electrostatic potential regions that were previously described.