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netLibrary - eBook Summary Structure-based Drug Design by ...

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Figure 8<br />

Schematic representation of the principal intermolecular<br />

interactions of cyclotheonamide A within the active site of<br />

thrombin.<br />

Page 255<br />

100 nM and represents a novel structural class of serine protease inhibitors. An x-ray crystal structure of<br />

CtA complexed with thrombin was used to determine the molecular basis for this inhibition (Figure 8<br />

[16]). The Arg-Pro unit binds to the S1 and S2 sites in a manner similar to the Arg-Pro of PPACK. The<br />

Arg guanidinium group forms a bidentate hydrogen bond with Asp189 while the Pro establishes a βsheet<br />

interaction with the Ser214-Gly216 backbone. The α-ketoamide acts as a transition-state mimetic<br />

forming a tetrahedral hemiketal with the hydroxyl of Ser195. Within the complex, CtA adopts a<br />

relatively open conformation with the Pro orthogonal to the macrocycle and confined <strong>by</strong> a hydrophobic<br />

pocket defined <strong>by</strong> Tyr60A, Trp60D, and Leu99. Two aromatic residues are involved in stacking<br />

interactions with Tyr60A and Trp60D. Cyclotheonamide A, however, does not effectively match the S3<br />

interactions provided <strong>by</strong> the D-Phe group found in PPACK. In CtA, the formamide group is too polar to<br />

effectively complement the S3 site adjacent to Trp215. The authors note that the complex of CtA with<br />

thrombin does not appear optimal and suggest that synthetic analogs could significantly improve both<br />

potency and selectivity.<br />

Starting with the known thrombin inhibitors Argatroban and Nα(2-naphthyl-sulfonyl-glycyl)-DL-pamidinophenylalanyl-piperidine<br />

(NAPAP), a group at Roche initiated a medicinal chemistry program to<br />

develop thrombin inhibitors with reduced toxicity and an improved hemodynamic profile [17].<br />

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