-transparent.png){kind=logo}
The inhibitory mechanism of trans-4-aminomethylcyclohexanecarbonyl-L-phenyl-alanine-4-carbo xymethylanilide (1), a noncovalent serine protease inhibitor synthesized based on previous structure-activity studies, was clarified based on the X-ray crystal structure of the complex (2.2 A resolution, R = 0.175), where the amino group of the aminomethylcyclohexane moiety was bifurcately hydrogen-bonded to the carboxyl oxygens of Asp 189 side group (specificity pocket), and the hydrogen bonds of the cyclohexanecarbonyl oxygen to NHs of Gly 193 and Ser 195 residues (oxyanion hole) and of Phe NH to Ser 195 O gamma atom (catalytic triad) were observed. In contrast, the Phe benzene moiety and terminal carboxymethylanilide of 1 were not well located on the electron density map, suggesting the conformational freedom of these P1' and P2' sites at the binding pocket. Based on these insights, trans-4-aminomethylcyclohexanecarbonyl-4-nitro-L-phenylalanine-4-+ ++benzoylanilide (2) was designed, in which the P1' and P2' sites were modified so as to effectively interact with the amino acid residues of trypsin binding pocket via hydrogen bonding and van der Waals interactions, respectively. Consequently, 2 showed 40 times higher inhibitory activity against trypsin than 1.
M Nakamura, and
K Tomoo, and
T Ishida, and
H Taguchi, and
Y Tsuda, and
Y Okada, and
A Okunomiya, and
K Wanaka, and
S Okamoto
February 1992,
FEBS letters,
M Nakamura, and
K Tomoo, and
T Ishida, and
H Taguchi, and
Y Tsuda, and
Y Okada, and
A Okunomiya, and
K Wanaka, and
S Okamoto
June 1989,
Journal of biochemistry,
M Nakamura, and
K Tomoo, and
T Ishida, and
H Taguchi, and
Y Tsuda, and
Y Okada, and
A Okunomiya, and
K Wanaka, and
S Okamoto
January 2004,
Biochemical and biophysical research communications,
M Nakamura, and
K Tomoo, and
T Ishida, and
H Taguchi, and
Y Tsuda, and
Y Okada, and
A Okunomiya, and
K Wanaka, and
S Okamoto
June 2013,
Journal of medicinal chemistry,
M Nakamura, and
K Tomoo, and
T Ishida, and
H Taguchi, and
Y Tsuda, and
Y Okada, and
A Okunomiya, and
K Wanaka, and
S Okamoto
July 2014,
Journal of natural products,
M Nakamura, and
K Tomoo, and
T Ishida, and
H Taguchi, and
Y Tsuda, and
Y Okada, and
A Okunomiya, and
K Wanaka, and
S Okamoto
April 2000,
Biological chemistry,
M Nakamura, and
K Tomoo, and
T Ishida, and
H Taguchi, and
Y Tsuda, and
Y Okada, and
A Okunomiya, and
K Wanaka, and
S Okamoto
January 1998,
Sheng wu hua xue yu sheng wu wu li xue bao Acta biochimica et biophysica Sinica,
M Nakamura, and
K Tomoo, and
T Ishida, and
H Taguchi, and
Y Tsuda, and
Y Okada, and
A Okunomiya, and
K Wanaka, and
S Okamoto
September 1998,
European journal of biochemistry,
M Nakamura, and
K Tomoo, and
T Ishida, and
H Taguchi, and
Y Tsuda, and
Y Okada, and
A Okunomiya, and
K Wanaka, and
S Okamoto
February 1983,
Journal of molecular biology,
M Nakamura, and
K Tomoo, and
T Ishida, and
H Taguchi, and
Y Tsuda, and
Y Okada, and
A Okunomiya, and
K Wanaka, and
S Okamoto
September 1998,
Journal of medicinal chemistry,
