| Abstract
| - We report the results of a three-dimensional quantitative structure−activity relationship (3D-QSAR) andpharmacophore modeling investigation of the interaction of the enzyme 3-phosphoglycerate kinase (PGK)with aryl and alkyl bisphosphonates. For the human enzyme, the IC50 values are predicted within a factorof 2 over the 240× experimental range in activity, while for the yeast enzyme, binding of the more flexiblealkyl bisphosphonates is predicted within a factor of ∼4 (over a 2500× range in activity). Pharmacophoremodels indicate the importance of two negative ionizable features, one hydrophobic feature, and one halogenfeature, and docking studies indicate that bisphosphonates bind in a manner similar to the 3-phosphoglyceratemolecule identified crystallographically. The results give a good account of the activities of a diverse rangeof bisphosphonate inhibitors and are of interest in the context of developing inhibitors of glycolysis inorganisms that are totally reliant on glycolysis for ATP production, such as trypanosomatid parasites.
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