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Document Page 160 hydrophobic, composed of residues Ala 116, Phe 200, and Val 217. The phosphate binding site uses residues Ser 33, Arg 84, His 86, and Ser 220 with the phosphate positioned for nucleophilic attack at C1' of the nucleoside. The sugar binding site is mostly hydrophobic consisting of residues Tyr 88, Phe 200, His 257 from one subunit and Phe 159 of the adjacent subunit. This hydrophobic pocket orients the sugar to facilitate nucleophilic attack by phosphate and subsequent inversion of C1'. C. Initial Inhibitor Complexes In order to understand the interaction of inhibitors with the active site residues, the previously known inhibitors were obtained and crystallographic analyses were carried out. The most important findings were (1) 8-amino substituents enhance binding of guanines by forming hydrogen bonds with Thr 242 and possibly the carbonyl oxygen atom of Ala 116; (2) substitution by hydrophobic groups at the 9position of a purine enhances binding through interaction with the hydrophobic region of the ribose binding site; and (3) acyclovir diphosphate is a multisubstrate inhibitor with the acyclic spacer between the purine N9 and the phosphate of near optimal length to accommodate these two binding sites. Based on these results, a number of starting compounds were proposed that incorporated these and other features predicted to enhance inhibitor binding. III. Molecular Modeling Structural information in combination with graphical methods for displaying accessible volume, electrostatic potential, and hydrophobicity of the active site of the target macromolecule greatly facilitates the drug design process. Accurate prediction of binding affinities and protein conformational changes are currently not routinely possible, although significant advances are being made. Proposed compounds were screened by modeling the enzyme-inhibitor complex using interactive computer graphics. Macromodel [21] and AMBER [22] based molecular energetics were used along with Monte Carlo/energy minimization techniques [23] to sample the conformational space available to potential inhibitors docked into the PNP active site. Methods based on the work of Goodford [24] employing custom software were also used. Qualitative evaluation of the enzyme-inhibitor complexes by molecular graphics and semiquantitative evaluation of the interaction energies between the inhibitors and the enzyme aided in the prioritization of compounds for chemical synthesis. http://legacy.netlibrary.com/nlreader/nlReader.dll?bookid=12640&filename=Page_160.html [4/5/2004 5:02:06 PM]
Document IV. Drug Design Progression Page 161 We focused initially on filling the purine binding region of the active site. That done, we planned to fill the sugar binding region and, finally, the phosphate binding site. We expected that each successive step, moving the compound closer toward fully occupying the active site, would enhance the affinity of the drug candidate for the enzyme. A. The Purine Site From our crystallographic examinations, we knew that three amino acids in the purine binding pocket of PNP formed hydrogen bonds with purines and their mimics. Such linkages are among the strongest reversible chemical bonds that exist. In proposing inhibitor candidates, we concentrated on compounds that would at least form hydrogen bonds with the same three amino acids. Figure 4e shows a close-up of the purine site. We favored exchanging a carbon atom for the nitrogen atom that normally occupies position nine, since there was no interaction of this nitrogen with the active site and earlier studies showed such a change promotes binding to PNP. Guanine modified in this way is called 9-deazaguanine. The first structures selected for synthesis were 9-deazaguanines substituted by an arylmethyl group at the 9 position. These compounds were prepared by adaption of a literature procedure [25]. We further expected that attaching an amino group to the carbon atom in position eight on 9-deazaguanine would enhance affinity, since 8aminoguanine was the first significant inhibitor of PNP. Both 8-aminoguanine analogs and 9-deazaguanine analogs are good inhibitors of PNP. However, introduction of an 8-amino group into the 9-deazaguanine derivatives resulted in decreased potency. To understand this poor binding, we undertook crystallographic analysis of PNP complexes with four compounds having the 9-thienyl substituent attached to guanine (G), 8-aminoguanine (8AG), 9deazaguanine (DG), and 8-amino-9-deazaguanine (8ADG). The results of this analysis are summarized in Figure 5. These data show one mode of binding for compounds that accept a hydrogen bond from Asn 243 at N7 (G and 8AG) and another for compounds that donate hydrogen to Asn 243 from N7 (DG and 8ADG). The 8AG analogs make use of the Thr 242 side chain to form an additional hydrogen bond, which improves binding affinity. In the 9-deazaguanine series, where N7 has an attached hydrogen atom, Asn 243 undergoes a shift that is clearly seen in difference Fourier maps. This shift is caused by the formation of the N7-H…OD(243) hydrogen bond. A concomitant shift by Thr 242 prevents it from hydrogen bonding to the 8-amino group of 8ADG. Furthermore, the shift moves the methyl group of Thr 242 towards the 8-amino http://legacy.netlibrary.com/nlreader/nlReader.dll?bookid=12640&filename=Page_161.html [4/5/2004 5:02:11 PM]
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Document [Protease targets] serinyl
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