The present study is a continuation of our efforts to use three-dimensional structures of parasitic phosphoribosyltransferases (PRTs) to design novel antiparasitic agents. All protozoan parasites lack the ability to synthesize purine nucleotides de novo.
Having previously reported on the successful design of selective ) were identified as the most active leads.
At this point we decided on the following two-stage strategy in our quest for GPRT ligands.
Guanine and the tetrasodium salt of PRPP were purchased from Sigma Chemical Co. Louis, Mo.) and are of the highest purity available., and concentrations were determined by integration of nuclear magnetic resonance peaks with methylene chloride as an internal standard. UC_Select (25) in combination with the Daylight version of the Available Chemicals Directory was used to identify original reagent sets, as well as for the elimination of reagents that had unattractive chemical or pharmaceutical properties.
The concentration of dimethyl sulfoxide in the assays was kept at 10%. Similarity and superstructure searches of the Available Chemicals Directory were performed with Daylight's Merlin system (version 4.61; Daylight Chemical Information Systems, Inc., Santa Fe, N.
In every case, the previously described (3) three-step docking procedure was used involving (i) library preorientation, followed by (ii) rigid docking and (iii) flexible scoring.