DMD #048264 1 Discovery and Characterization of Novel, Potent ...

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DMD #048264 Footnotes This work was supported by National Key Project [Grants 2010CB945501, 2010CB912604]; National Science Foundation of China [Grant 21173082]; Shanghai Rising-Star Program [Grant 11QA1402000]; National Natural Science Foundation of China [Grants 10974054, 20933002]; and Shanghai Pujiang Program [Grant 09PJ1404000]. 34
DMD #048264 Figure Legends FIGURE 1. Representative IC50 plots for telmisartan (A) and flunarizine (B) inhibition of astemizole O-demethylation using recombinant CYP2J2 with astemizole concentrations from 0.1 to 20 μM. FIGURE 2. Disappearance of astemizole (A), telmisartan (B), and flunarizine (C) measured from incubation with recombinant CYP2J2 in the presence of NADPH at different time points (n = 2). FIGURE 3. IC50 determination of inhibition of CYP2J2-mediated astemizole O- demethylation by telmisartan (A) and flunarizine (B) in the presence and absence of NADPH. The inhibitors were pre-incubated with CYP2J2 for 30 minutes. The IC50 shift was calculated as IC50 in the absence of NADPH over IC50 in the presence of NADPH in order to evaluate time-dependent inhibition. FIGURE 4. Inhibition assay against the enzymatic activity of recombinant CYP2J2. Non-linear regression of the initial velocity at various substrate concentrations under the presence of telmisartan (A) and flunarizine (B) as the inhibitor with concentrations from 0.1 to 2 μM and from 0.2 to 5 μM, respectively. Dixon plots with amplified insets for the enzyme kinetic study of CYP2J2-mediated astemizole O-demethylation in the presence of different concentrations of telmisartan (C) and flunarizine (D) as the inhibitor. Astemizole concentrations used were 0.05 (●), 0.1 (□), 0.15 (▲), 0.3 (◇), and 0.45 μM 35
Page 1 and 2: DMD Fast Forward. Published on Octo
Page 3 and 4: DMD #048264 Abstract Cytochrome P45
Page 5 and 6: DMD #048264 its rather broad substr
Page 7 and 8: DMD #048264 role of CYP2J2 in drug
Page 9 and 10: DMD #048264 CYP2C9, CYP2C19, and CY
Page 11 and 12: DMD #048264 AST, DES-AST, and IS, r
Page 13 and 14: DMD #048264 where v is the reaction
Page 15 and 16: DMD #048264 = ΔEelec + ΔEvdW + Δ
Page 17 and 18: DMD #048264 Paine et al., 2006) and
Page 19 and 20: DMD #048264 plot does not go throug
Page 21 and 22: DMD #048264 surface for telmisartan
Page 23 and 24: DMD #048264 given its predominant e
Page 25 and 26: DMD #048264 subsequently confirmed
Page 27 and 28: DMD #048264 activity by restraining
Page 29 and 30: DMD #048264 References Baron A, Fri
Page 31 and 32: DMD #048264 Lafite P, Dijols S, Zel
Page 33: DMD #048264 Young CL, Dias VC, and
Page 37 and 38: DMD #048264 segment (Ile376, Pro377
Page 39 and 40: DMD #048264 Table 2: Probe substrat
Page 41: DMD #048264 Table 4: Binding free e

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