COMPARATIVE MOLECULAR-FIELD ANALYSIS OF COMPOUNDS WITH CYP2A5 BINDING-AFFINITY

Sixteen planar coumarin type substrates and inhibitors of cytochrome P 4502A5 (CYP2A5) were analyzed using the Comparative Molecular Field An alysis (CoMFA) method [1]. The analysis was carried out using traditio nal steric and electrostatic fields, the energy of the lowest unoccupi ed molecular orbital (LUMO) and the highest occupied molecular orbital (HOMO), dipole moment and LUMO as a 3-D field (square of the wave fun ction). The highest cross-validated r(2)-value (q(2)), 0.741. was obta ined (five PLS components) when steric and electrostatic fields were u sed together. However, when LUMO field or energy was included in the a nalyses, q(2)-values decreased (0.723 and 0.724, respectively) and the required number of PLS components also decreased to three. In this ca se the LUMO field most probably reflects structural information not sh own in traditional fields. CoMFA contour maps emphasized the importanc e of the ligands' lactone structure, together with the methoxy group o f methoxsalen, for high CYP2A5 binding affinity.