Design of potent bisphosphonate inhibitors of the human farnesyl pyrophosphate synthase via targeted interactions with the active site 'capping' phenyls.

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De Schutter JW, Shaw J, Lin YS, Tsantrizos YS

Design of potent bisphosphonate inhibitors of the human farnesyl pyrophosphate synthase via targeted interactions with the active site 'capping' phenyls.

Bioorg Med Chem. 2012 Sep 15;20(18):5583-91. doi: 10.1016/j.bmc.2012.07.019. Epub 2012 Jul 24.

PubMed ID

22884353 [ View in PubMed

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Abstract

Nitrogen-containing bisphosphonates (N-BPs) are potent active site inhibitors of the human farnesyl pyrophosphate synthase (hFPPS) and valuable human therapeutics for the treatment of bone-related malignancies. N-BPs are also useful in combination chemotherapy for patients with breast, prostate and multiple myeloma cancers. A structure-based approach was employed in order to design inhibitors that exhibit higher lipophilicity and better occupancy for the GPP sub-pocket of hFPPS than the current therapeutic drugs. These novel analogs were designed to bind deeper into the GPP sub-pocket by displacing the side chains of the 'capping' residue Phe 113 and engaging in favorable pi-interactions with the side chain of Phe112.

DrugBank Data that Cites this Article

Binding Properties

Drug	Target	Property	Measurement	pH	Temperature (°C)
Risedronic acid	Farnesyl pyrophosphate synthase	IC 50 (nM)	11	N/A	N/A	Details