A comparative molecular field analysis of cytochrome P450 2A5 and 2A6 inhibitors

Structure-activity relationships of 23 P450 2A5 and 2A6 inhibitors were ana lysed using the CoMFA [1] and GOLPE/GRID with smart region definition (SRD) [2]. The predictive power of the resulting models was validated using five compounds not belonging to the model set. All models have high internal an d external predictive power and resulting 3D-QSAR models are supporting eac h other. Both Sybyl and GOLPE highlight properties near lactone moiety to b e important for 2A5 and 2A6 inhibition. Another important feature for pIC(5 0) was the size of the substituent in the 7-positon of coumarin. The models suggest that the 2A5 binding site is larger that that of 2A6 due to larger steric regions in the CoMFA coefficient maps and corresponding GOLPE maps. In addition, the maps reveal that 2A6 disfavours negative charge near the lactone moiety of coumarin.