Bisphosphonate inhibition of phosphoglycerate kinase: quantitative structure-activity relationship and pharmacophore...

We report the results of a three-dimensional quantitative structure-activity relationship (3D-QSAR) and pharmacophore 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 factor of 2 over the 240x experimental range in activity, while for the yeast enzyme, binding of the more flexible alkyl bisphosphonates is predicted within a factor of approximately 4 (over a 2500x range in activity). Pharmacophore models indicate the importance of two negative ionizable features, one hydrophobic feature, and one halogen feature, and docking studies indicate that bisphosphonates bind in a manner similar to the 3-phosphoglycerate molecule identified crystallographically. The results give a good account of the activities of a diverse range of bisphosphonate inhibitors and are of interest in the context of developing inhibitors of glycolysis in organisms that are totally reliant on glycolysis for ATP production, such as trypanosomatid parasites.