Dataset Information

Design, synthesis, calorimetry, and crystallographic analysis of 2-alkylaminoethyl-1,1-bisphosphonates as inhibitors of Trypanosoma cruzi farnesyl diphosphate synthase.

ABSTRACT: Linear 2-alkylaminoethyl-1,1-bisphosphonates are effective agents against proliferation of Trypanosoma cruzi , the etiologic agent of American trypanosomiasis (Chagas disease), exhibiting IC(50) values in the nanomolar range against the parasites. This activity is associated with inhibition at the low nanomolar level of the T. cruzi farnesyl diphosphate synthase (TcFPPS). X-ray structures and thermodynamic data of the complexes TcFPPS with five compounds of this family show that the inhibitors bind to the allylic site of the enzyme, with their alkyl chain occupying the cavity that binds the isoprenoid chain of the substrate. The compounds bind to TcFPPS with unfavorable enthalpy compensated by a favorable entropy that results from a delicate balance between two opposing effects: the loss of conformational entropy due to freezing of single bond rotations and the favorable burial of the hydrophobic alkyl chains. The data suggest that introduction of strategically placed double bonds and methyl branches should increase affinity substantially.

SUBMITTER: Aripirala S

PROVIDER: S-EPMC4710095 | biostudies-literature | 2012 Jul

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Design, synthesis, calorimetry, and crystallographic analysis of 2-alkylaminoethyl-1,1-bisphosphonates as inhibitors of Trypanosoma cruzi farnesyl diphosphate synthase.

Aripirala Srinivas S Szajnman Sergio H SH Jakoncic Jean J Rodriguez Juan B JB Docampo Roberto R Gabelli Sandra B SB Amzel L Mario LM

Journal of medicinal chemistry 20120705 14

Linear 2-alkylaminoethyl-1,1-bisphosphonates are effective agents against proliferation of Trypanosoma cruzi , the etiologic agent of American trypanosomiasis (Chagas disease), exhibiting IC(50) values in the nanomolar range against the parasites. This activity is associated with inhibition at the low nanomolar level of the T. cruzi farnesyl diphosphate synthase (TcFPPS). X-ray structures and thermodynamic data of the complexes TcFPPS with five compounds of this family show that the inhibitor ...[more]

PMID: 22715997

Similar Datasets

Project description:Human farnesyl pyrophosphate synthase (hFPPS) catalyzes the production of the 15-carbon isoprenoid farnesyl pyrophosphate. The enzyme is a key regulator of the mevalonate pathway and a well-established drug target. Notably, it was elucidated as the molecular target of nitrogen-containing bisphosphonates, a class of drugs that have been widely successful against bone resorption disorders. More recently, research has focused on the anticancer effects of these inhibitors. In order to achieve increased non-skeletal tissue exposure, we created phenylaminopyridine bisphosphonates (PNP-BPs) that have bulky hydrophobic side chains through a structure-based approach. Some of these compounds have proven to be more potent than the current clinical drugs in a number of antiproliferation assays using multiple myeloma cell lines. In the present work, we characterized the binding of our most potent PNP-BPs to the target enzyme, hFPPS. Co-crystal structures demonstrate that the molecular interactions designed to elicit tighter binding are indeed established. We carried out thermodynamic studies as well; the newly introduced protein-ligand interactions are clearly reflected in the enthalpy of binding measured, which is more favorable for the new PNP-BPs than for the lead compound. These studies also indicate that the affinity of the PNP-BPs to hFPPS is comparable to that of the current drug risedronate. Risedronate forms additional polar interactions via its hydroxyl functional group and thus exhibits more favorable binding enthalpy; however, the entropy of binding is more favorable for the PNP-BPs, owing to the greater desolvation effects resulting from their large hydrophobic side chains. These results therefore confirm the overall validity of our drug design strategy. With a distinctly different molecular scaffold, the PNP-BPs described in this report represent an interesting new group of future drug candidates. Further investigation should follow to characterize the tissue distribution profile and assess the potential clinical benefits of these compounds.

Dataset Information

Design, synthesis, calorimetry, and crystallographic analysis of 2-alkylaminoethyl-1,1-bisphosphonates as inhibitors of Trypanosoma cruzi farnesyl diphosphate synthase.

Publications

Design, synthesis, calorimetry, and crystallographic analysis of 2-alkylaminoethyl-1,1-bisphosphonates as inhibitors of Trypanosoma cruzi farnesyl diphosphate synthase.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets