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Document e Guanine base. Source: Ref. 27. with a two-carbon spacer was a much better PNP inhibitor; however, it was clear from x-ray analysis that the aromatic ring was unable to form the ideal “herringbone” packing interaction. Alternatively, compounds were modeled in which the spacer to the phosphate binding site branched from the benzylic carbon, thus placing no restrictions on the tilt of the aromatic ring. Examination of the 9-benzyl-9-deazaguanine/PNP complex indicated that of the two benzylic positions, one (pro-R) pointed into a sterically crowded area within the active site, whereas the other (pro-S) pointed into a relatively empty space adjacent to the phosphate binding site. This analysis led to the synthesis of racemic 9-[1-(3chlorophenyl)-2-carboxyethyl]-9-deazaguanine. This compound adds an acetate group (CH 2COO-) to the methylene carbon atom that joined 9-deazaguanine to the chlorinated benzene ring. This compound was resolved into its (S) and (R) enantiomers. http://legacy.netlibrary.com/nlreader/nlReader.dll?bookid=12640&filename=Page_165.html (2 of 2) [4/5/2004 5:02:28 PM]
Document Page 166 As predicated, the (S) acid was a 30-fold more potent inhibitor of PNP than the (R) form. X-ray crystallographic analysis of the complexes revealed that the (S) acid was oriented properly for optimal interactions with all three subsites (Figure 4F), whereas the (R) acid was not. This series of compounds contains the most potent membrane-permeable inhibitors of PNP yet reported [27]. V. Summary Recently, scientists at BioCryst have successfully completed a project to design and synthesize potent inhibitors of the enzyme Purine Nucleoside Phosphorylase (PNP) using the three-dimensional structure of the active site. Crystallographic and modeling methods have been combined with organic synthesis to produce inhibitors. Our experience in creating a set of potential drugs—one of which (BCX-34) is now in human trials for treating psoriasis and a form of T-cell lymphoma—illustrates the process and the power of structure-based design. This structure-based inhibitor design approach led to a number of inhibitors more than 100 times more potent than any membrane-permeable inhibitor available at the beginning of this project. During the two and half years of this project, about 60 active compounds were synthesized. This is a remarkably small number compared with the extensive synthesis programs generally involved in drug discovery by trial and error techniques. The large number of active compounds and the enhancement of inhibitor potency stand as proof that crystallographic and modeling techniques are now capable of playing a critical role in the rapid discovery of novel therapeutic agents. The entire protocol, from choosing the target to creating a drug suitable for clinical trials, can probably be accomplished today in two or three years. A. Obstacles Encountered and Lessons Learned Crystallographic analysis was based primarily on the results of difference Fourier maps in which the interactions between residues in the active site and the inhibitor could be characterized. During these studies, about 35 inhibitor complexes were evaluated by x-ray crystallographic techniques. It is noteworthy that the resolution of the PNP model extends to only 2.8 Å and that all of the difference Fourier maps were calculated at 3.2 Å resolution, much lower than often considered essential for drug design. Crystallographic analysis was facilitated by the large solvent content that allowed for free diffusion of inhibitors into enzymatically active crystals. Initial inhibitor modeling attempts using the native PNP structure were far less successful than subsequent analyses in which coordinates for the guanine- http://legacy.netlibrary.com/nlreader/nlReader.dll?bookid=12640&filename=Page_166.html [4/5/2004 5:02:29 PM]
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Document D ddI, 152 tumour necrosis
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Document antistasin peptides, 281 c
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Document fragment-based programs, 5
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Document Phosphoglycerate kinase (P
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Document [Protease targets] serinyl
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