Dipeptide Side Chain-Side Chain Hydrophobic Interactions as Conformational Core for Chymotrypsin Inhibition.

概要

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A series of dipeptides with the sequence of H–D-Leu–L-Phe–R, where R denotes 4-phenylpiperidide, 4-phenylpiperazide, and their derivatives, have been synthesized to examine their ability to inhibit chymotrypsin. Dipeptide phenylpiperidide and phenylpiperazide inhibited chymotrypsin fairly strongly (Ki=7.5×10−4 M and 1.4×10−3 M, respectively) (1 M=l mol dm−3), while their phenyl-substituted analogs were inactive. In high resolution 3H NMR measurements, it was found that the proton signals of D-Leu γ-CH and β-CH2 shifted considerably to the upfield when compared with those of H–D-Leu–L-Ala–OH, suggesting that these upfield shifts are due to the magnetic anisotropy effect by the benzene ring of the Phe residue. This was confirmed by measuring NOE between D-Leu–isobutyl and L-Phe–phenyl groups. These NMR data indicate that the side chains of both D-Leu and L-Phe are in close proximity, resulting in formation of a hydrophobic complex. It was suggested that, in the inhibitory conformation of dipeptides against chymotrypsin, the phenyl group of phenylpiperidide or phenylpiperazide moiety fits the S1 site, while the side chain-side chain hydrophobic complexing core fits the S2 site.
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