Rational Design of Selective Submicromolar Inhibitors of Tritrichomonas foetus Hypoxanthine-Guanine-Xanthine Phosphoribosyltransferase
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- 作者：Alex M. Aronov ; Narsimha R. Munagala ; Paul R. Ortiz de Montellano ; Irwin D. Kuntz ; and Ching C. Wang
- 刊名：Biochemistry
- 出版年：2000
- 出版时间：April 25, 2000
- 年：2000
- 卷：39
- 期：16
- 页码：4684 - 4691
- 全文大小：201K
- 年卷期：v.39,no.16(April 25, 2000)
- ISSN：1520-4995
文摘
All parasitic protozoa lack the ability to synthesize purine nucleotides de novo, relying insteadon purine salvage enzymes for their survival. Hypoxanthine-guanine-xanthine phosphoribosyltransferase(HGXPRT) from the protozoan parasite Tritrichomonas foetus is a rational target for antiparasitic drugdesign because it is the primary enzyme the parasite uses to salvage purine bases from the host. Thestudy presented here is a continuation of our efforts to use the X-ray structure of the T. foetus HGXPRT-GMP complex to design compounds that bind tightly to the purine pocket of HGXPRT. The goal of thecurrent project was to improve the affinity and selectivity of previously identified HGXPRT inhibitorTF1 [4-(3-nitroanilino)phthalic anhydride]. A virtual library of substituted 4-phthalimidocarboxanilideswas constructed using methods of structure-based drug design, and was implemented synthetically onsolid support. Compound 20 [(4'-phthalimido)carboxamido-3-benzyloxybenzene] was then used as asecondary lead for the second round of combinatorial chemistry, producing a number of low-micromolarinhibitors of HGXPRT. One of these compounds, TF2 [(4'-phthalimido)carboxamido-3-(4-bromobenzyloxy)benzene], was further characterized as a competitive inhibitor of T. foetus HGXPRT with respect toguanine with a KI of 0.49 
mages/entities/mgr.gif">M and a 30-fold selectivity over the human HGPRT. TF2 inhibited the growthof cultured T. foetus cells in a concentration-dependent manner with an ED50 of 2.8 mages/entities/mgr.gif">M, and this inhibitoryeffect could be reversed by addition of exogenous hypoxanthine. These studies underscore the efficiencyof combining structure-based drug design with combinatorial chemistry to produce effective species-specific enzyme inhibitors of medicinal importance.