Fig. 5.

Superposition of the hydrophobic pocket residues in the substrate access channel of human iNOSoxy (green), human eNOSoxy (magenta), and the homology model of human nNOSoxy (gray). The reference structure of AR-R17477 from rat nNOSoxy-AR-R17477 is shown in dark-gray (model 1). The QM/MM optimized models of modified AR-R17477 are shown in black (model 2 containing a chloropyridine ring) and orange (model 3 containing a hydroxypyridine ring). In models 2 and 3, the pyridine nitrogen can form a hydrogen bond with the side chains of both H342 (human nNOS) and T121 (human iNOS). The phenyl ring of F105 (human eNOS) does not allow such an interaction and should preserve the “push-out” effect described in the text. The red balls represent the water molecules from the human iNOSoxy crystal structure that overlap with AR-R17477 atoms in this region.