Design, synthesis, calorimetry, and crystallographic analysis of 2-alkylaminoethyl-1,1-bisphosphonates as inhibitors of trypanosoma cruzi farnesyl diphosphate synthase
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...
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todo:paper_00222623_v55_n14_p6445_Aripirala2023-10-03T14:30:16Z Design, synthesis, calorimetry, and crystallographic analysis of 2-alkylaminoethyl-1,1-bisphosphonates as inhibitors of trypanosoma cruzi farnesyl diphosphate synthase Aripirala, S. Szajnman, S.H. Jakoncic, J. Rodriguez, J.B. Docampo, R. Gabelli, S.B. Amzel, L.M. alkyl group allyl compound amine antitrypanosomal agent bisphosphonic acid derivative geranyltransferase geranyltransferase inhibitor isoprenoid methyl group unclassified drug article binding affinity Chagas disease chemical bond complex formation conformation crystal structure drug design drug protein binding drug synthesis enthalpy entropy enzyme active site enzyme inhibition hydrophobicity IC 50 isothermal titration calorimetry nonhuman structure activity relation thermodynamics Trypanosoma cruzi X ray crystallography Calorimetry Crystallography, X-Ray Drug Design Enzyme Inhibitors Geranyltranstransferase Magnesium Models, Molecular Phosphonic Acids Protein Conformation Thermodynamics Trypanosoma cruzi 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. © 2012 American Chemical Society. Fil:Szajnman, S.H. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales; Argentina. Fil:Rodriguez, J.B. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales; Argentina. Fil:Amzel, L.M. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales; Argentina. JOUR info:eu-repo/semantics/openAccess http://creativecommons.org/licenses/by/2.5/ar http://hdl.handle.net/20.500.12110/paper_00222623_v55_n14_p6445_Aripirala |
| institution |
Universidad de Buenos Aires |
| institution_str |
I-28 |
| repository_str |
R-134 |
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Biblioteca Digital - Facultad de Ciencias Exactas y Naturales (UBA) |
| topic |
alkyl group allyl compound amine antitrypanosomal agent bisphosphonic acid derivative geranyltransferase geranyltransferase inhibitor isoprenoid methyl group unclassified drug article binding affinity Chagas disease chemical bond complex formation conformation crystal structure drug design drug protein binding drug synthesis enthalpy entropy enzyme active site enzyme inhibition hydrophobicity IC 50 isothermal titration calorimetry nonhuman structure activity relation thermodynamics Trypanosoma cruzi X ray crystallography Calorimetry Crystallography, X-Ray Drug Design Enzyme Inhibitors Geranyltranstransferase Magnesium Models, Molecular Phosphonic Acids Protein Conformation Thermodynamics Trypanosoma cruzi |
| spellingShingle |
alkyl group allyl compound amine antitrypanosomal agent bisphosphonic acid derivative geranyltransferase geranyltransferase inhibitor isoprenoid methyl group unclassified drug article binding affinity Chagas disease chemical bond complex formation conformation crystal structure drug design drug protein binding drug synthesis enthalpy entropy enzyme active site enzyme inhibition hydrophobicity IC 50 isothermal titration calorimetry nonhuman structure activity relation thermodynamics Trypanosoma cruzi X ray crystallography Calorimetry Crystallography, X-Ray Drug Design Enzyme Inhibitors Geranyltranstransferase Magnesium Models, Molecular Phosphonic Acids Protein Conformation Thermodynamics Trypanosoma cruzi Aripirala, S. Szajnman, S.H. Jakoncic, J. Rodriguez, J.B. Docampo, R. Gabelli, S.B. Amzel, L.M. Design, synthesis, calorimetry, and crystallographic analysis of 2-alkylaminoethyl-1,1-bisphosphonates as inhibitors of trypanosoma cruzi farnesyl diphosphate synthase |
| topic_facet |
alkyl group allyl compound amine antitrypanosomal agent bisphosphonic acid derivative geranyltransferase geranyltransferase inhibitor isoprenoid methyl group unclassified drug article binding affinity Chagas disease chemical bond complex formation conformation crystal structure drug design drug protein binding drug synthesis enthalpy entropy enzyme active site enzyme inhibition hydrophobicity IC 50 isothermal titration calorimetry nonhuman structure activity relation thermodynamics Trypanosoma cruzi X ray crystallography Calorimetry Crystallography, X-Ray Drug Design Enzyme Inhibitors Geranyltranstransferase Magnesium Models, Molecular Phosphonic Acids Protein Conformation Thermodynamics Trypanosoma cruzi |
| description |
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. © 2012 American Chemical Society. |
| format |
JOUR |
| author |
Aripirala, S. Szajnman, S.H. Jakoncic, J. Rodriguez, J.B. Docampo, R. Gabelli, S.B. Amzel, L.M. |
| author_facet |
Aripirala, S. Szajnman, S.H. Jakoncic, J. Rodriguez, J.B. Docampo, R. Gabelli, S.B. Amzel, L.M. |
| author_sort |
Aripirala, S. |
| title |
Design, synthesis, calorimetry, and crystallographic analysis of 2-alkylaminoethyl-1,1-bisphosphonates as inhibitors of trypanosoma cruzi farnesyl diphosphate synthase |
| title_short |
Design, synthesis, calorimetry, and crystallographic analysis of 2-alkylaminoethyl-1,1-bisphosphonates as inhibitors of trypanosoma cruzi farnesyl diphosphate synthase |
| title_full |
Design, synthesis, calorimetry, and crystallographic analysis of 2-alkylaminoethyl-1,1-bisphosphonates as inhibitors of trypanosoma cruzi farnesyl diphosphate synthase |
| title_fullStr |
Design, synthesis, calorimetry, and crystallographic analysis of 2-alkylaminoethyl-1,1-bisphosphonates as inhibitors of trypanosoma cruzi farnesyl diphosphate synthase |
| title_full_unstemmed |
Design, synthesis, calorimetry, and crystallographic analysis of 2-alkylaminoethyl-1,1-bisphosphonates as inhibitors of trypanosoma cruzi farnesyl diphosphate synthase |
| title_sort |
design, synthesis, calorimetry, and crystallographic analysis of 2-alkylaminoethyl-1,1-bisphosphonates as inhibitors of trypanosoma cruzi farnesyl diphosphate synthase |
| url |
http://hdl.handle.net/20.500.12110/paper_00222623_v55_n14_p6445_Aripirala |
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