Structural Studies of Nitric Oxide Synthase Inhibitor Complexes: An Anchored Plasticity Approach for Selective Enzyme Inhibition
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چکیده
Figure 1. NOS inhibitors. X-ray structures of 6 inhibitors bound to iNOS (a-c) and eNOS (d) representative of three different pharmacophores used in this study. (a) Binding mode of small (1) and large (3) quinazolines to iNOS. (b) Binding mode of small (6) and large (9) aminopyridines to iNOS. (c) Binding mode of small (14) and large (16) bicyclic thienooxazepines to iNOS. Binding of the large inhibitors induces the cascade of conformational changes (arrow) and opening of the new specificity pocket. (d) Binding mode of inhibitor 9 in iNOS (blue) and eNOS (yellow) showing the absence of conformational changes in eNOS. Boxed residues represent the isozyme-specific triad of distant residues that modulate the opening of the pocket. (e) Structures and inhibitory potencies of 6 of the inhibitors used in this study. The inhibitor core is shown in black and the “tail” in magenta. IC50 values are shown for all three isozymes. Structural Studies of Nitric Oxide Synthase Inhibitor Complexes: An Anchored Plasticity Approach for Selective Enzyme Inhibition
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