Bisphosphonate Inhibition of a Plasmodium Farnesyl Diphosphate Synthase and a General Method for Predicting Cell-Based Activity from Enzyme Data

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 pIC50(cell) = a pIC50(enzyme)...

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Bibliographic Details
Published in:Journal of medicinal chemistry 2008-12, Vol.51 (24), p.7827-7833
Main Authors: Mukkamala, Dushyant, No, Joo Hwan, Cass, Lauren M, Chang, Ting-Kai, Oldfield, Eric
Format: Article
Language:English
Subjects:
Animals
Anti-Bacterial Agents - pharmacology
Antiviral Agents - pharmacology
Biological and medical sciences
Cell Line, Tumor
Dictyostelium - metabolism
Diphosphonates - pharmacology
Drug Design
Drug Evaluation, Preclinical
Enzyme Inhibitors - chemistry
Enzyme Inhibitors - pharmacology
Geranyltranstransferase - antagonists & inhibitors
Geranyltranstransferase - chemistry
Humans
Inhibitory Concentration 50
Leishmania donovani - metabolism
Medical sciences
Miscellaneous
Models, Chemical
Pharmacology. Drug treatments
Plasmodium vivax - enzymology
Predictive Value of Tests
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Summary: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 pIC50(cell) = a pIC50(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 pIC50 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 ∼0.02 to 0.72.
ISSN:0022-2623
1520-4804
DOI:10.1021/jm8009074