title: Bisphosphonate inhibition of a Plasmodium farnesyl diphosphate synthase and a general method for predicting cell-based activity from enzyme data.
abstract: We screened 26 bisphosphonates against a farnesyl diphosphate synthase from Plasmodium vivax, finding a poor correlation between enzyme and cell growth inhibition (R(2) = 0.06). To better predict cell activity data, we then used a combinatorial descriptor search in which pIC(50)(cell) = a pIC(50)(enzyme) + bB + cC + d, where B and C are descriptors (such as SlogP), and a-d are coefficients. R(2) increased from 0.01 to 0.74 (for a leave-two-out test set of 26 predictions). The method was then further validated using data for nine other systems, including bacterial, viral, and mammalian cell systems. On average, experimental/predicted cell pIC(50) correlations increased from R(2) = 0.28 (for an enzyme-only test set) to 0.70 (for enzyme plus two descriptor test set predictions), while predictions based on scrambled cell activity had no predictive value (R(2) = 0.13). These results are of interest since they represent a general way to predict cell from enzyme inhibition data, with in three cases, R(2) values increasing from approximately 0.02 to 0.72.
authors.affiliation: Center for Biophysics and Computational Biology, University of Illinois at Urbana-Champaign, 600 South Mathews Avenue, Urbana, Illinois 61801, USA.
authors.forename: Dushyant
authors.initials: D
authors.lastname: Mukkamala
authors.forename: Joo Hwan
authors.initials: JH
authors.lastname: No
authors.forename: Lauren M
authors.initials: LM
authors.lastname: Cass
authors.forename: Ting-Kai
authors.initials: TK
authors.lastname: Chang
authors.forename: Eric
authors.initials: E
authors.lastname: Oldfield
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000494:pharmacology; D000998:Antiviral Agents / Q000494:pharmacology; D045744:Cell Line, Tumor; D004023:Dictyostelium / Q000378:metabolism; D004164:Diphosphonates / Q000494:pharmacology*; D015195:Drug Design; D004353:Drug Evaluation, Preclinical; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D051228:Geranyltranstransferase / Q000037:antagonists & inhibitors / Q000737:chemistry*; D006801:Humans; D020128:Inhibitory Concentration 50; D007893:Leishmania donovani / Q000378:metabolism; D008956:Models, Chemical; D010966:Plasmodium vivax / Q000201:enzymology*; D011237:Predictive Value of Tests
chemical_list: D000900:Anti-Bacterial Agents; D000998:Antiviral Agents; D004164:Diphosphonates; D004791:Enzyme Inhibitors; D051228:Geranyltranstransferase