title: Virtual screening of combinatorial libraries across a gene family: in search of inhibitors of Giardia lamblia guanine phosphoribosyltransferase.
abstract: Parasitic protozoa lack the ability to synthesize purine nucleotides de novo, relying instead on purine salvage enzymes for their survival. Guanine phosphoribosyltransferase (GPRT) from the protozoan parasite Giardia lamblia is a potential target for rational antiparasitic drug design, based on the experimental evidence, which indicates the lack of interconversion between adenine and guanine nucleotide pools. The present study is a continuation of our efforts to use three-dimensional structures of parasitic phosphoribosyltransferases (PRTs) to design novel antiparasitic agents. Two micromolar phthalimide-based GPRT inhibitors were identified by screening the in-house phthalimide library. A combination of structure-based scaffold selection using virtual library screening across the PRT gene family and solid phase library synthesis led to identification of smaller (molecular weight, <300) ligands with moderate to low specificity for GPRT; the best inhibitors, GP3 and GP5, had K(i) values in the 23 to 25 microM range. These results represent significant progress toward the goal of designing potent inhibitors of purine salvage in Giardia parasites. As a second step in this process, altering the phthalimide moiety to optimize interactions in the guanine-binding pocket of GPRT is expected to lead to compounds with promising activity against G. lamblia PRT.
authors.affiliation: Department of Pharmaceutical Chemistry, University of California, San Francisco, California 94143-0446, USA.
authors.forename: A M
authors.initials: AM
authors.lastname: Aronov
authors.forename: N R
authors.initials: NR
authors.lastname: Munagala
authors.forename: I D
authors.initials: ID
authors.lastname: Kuntz
authors.forename: C C
authors.initials: CC
authors.lastname: Wang
mesh_terms: D000818:Animals; D000977:Antiparasitic Agents / Q000737:chemistry / Q000494:pharmacology*; D015195:Drug Design; D016829:Giardia lamblia / Q000187:drug effects / Q000201:enzymology*; D007041:Hypoxanthine Phosphoribosyltransferase / Q000037:antagonists & inhibitors* / Q000737:chemistry; D008958:Models, Molecular; D021261:Parasitic Sensitivity Tests; D010797:Phthalimides / Q000737:chemistry / Q000494:pharmacology*; D011487:Protein Conformation; D013329:Structure-Activity Relationship
chemical_list: D000977:Antiparasitic Agents; D010797:Phthalimides; D007041:Hypoxanthine Phosphoribosyltransferase