Comparative molecular field analysis of compounds with CYP2A5 binding affinity

Sixteen planar coumarin type substrates and inhibitors of cytochrome P4502A5 (CYP2A5) were analyzed using the Comparative Molecular Field Analysis (CoMFA) method [1]. The analysis was carried out using traditional steric and electrostatic fields, the energy of the lowest unoccupied molecular orbital (LUMO) and the highest occupied molecular orbital (HOMO), dipole moment and LUMO as a 3-D field (square of the wave function). The highest cross-validated r(2)-value (q(2)), 0.741. was obtained (five PLS components) when steric and electrostatic fields were used together. However, when LUMO field or energy was included in the analyses, q(2)-values decreased (0.723 and 0.724, respectively) and the required number of PLS components also decreased to three. In this case the LUMO field most probably reflects structural information not shown in traditional fields. CoMFA contour maps emphasized the importance of the ligands' lactone structure, together with the methoxy group of methoxsalen, for high CYP2A5 binding affinity.