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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. © 2012 American Chemical Society.

Registro:

Documento: Artículo
Título:Design, synthesis, calorimetry, and crystallographic analysis of 2-alkylaminoethyl-1,1-bisphosphonates as inhibitors of trypanosoma cruzi farnesyl diphosphate synthase
Autor:Aripirala, S.; Szajnman, S.H.; Jakoncic, J.; Rodriguez, J.B.; Docampo, R.; Gabelli, S.B.; Amzel, L.M.
Filiación:Department of Biophysics and Biophysical Chemistry, Johns Hopkins University School of Medicine, Baltimore, MD 21205, United States
Brookhaven National Laboratory, National Synchrotron Light Source, Upton, NY 11973, United States
Departamento de Química Orgánica and UMYMFOR (CONICET-FCEyN), Facultad de Ciencias Exactas y Naturales, Ciudad Universitaria, Pabellón 2, C1428EHA Buenos Aires, Argentina
Center for Tropical and Global Emerging Diseases, Department of Cellular Biology, University of Georgia, Athens, GA 30606, United States
Palabras clave: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
Año:2012
Volumen:55
Número:14
Página de inicio:6445
Página de fin:6454
DOI: http://dx.doi.org/10.1021/jm300425y
Título revista:Journal of Medicinal Chemistry
Título revista abreviado:J. Med. Chem.
ISSN:00222623
CODEN:JMCMA
CAS:geranyltransferase, 37277-79-5, 50812-36-7; Enzyme Inhibitors; Geranyltranstransferase, 2.5.1.10; Magnesium, 7439-95-4; Phosphonic Acids
Registro:https://bibliotecadigital.exactas.uba.ar/collection/paper/document/paper_00222623_v55_n14_p6445_Aripirala

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Citas:

---------- APA ----------
Aripirala, S., Szajnman, S.H., Jakoncic, J., Rodriguez, J.B., Docampo, R., Gabelli, S.B. & Amzel, L.M. (2012) . Design, synthesis, calorimetry, and crystallographic analysis of 2-alkylaminoethyl-1,1-bisphosphonates as inhibitors of trypanosoma cruzi farnesyl diphosphate synthase. Journal of Medicinal Chemistry, 55(14), 6445-6454.
http://dx.doi.org/10.1021/jm300425y
---------- CHICAGO ----------
Aripirala, S., Szajnman, S.H., Jakoncic, J., Rodriguez, J.B., Docampo, R., Gabelli, S.B., et al. "Design, synthesis, calorimetry, and crystallographic analysis of 2-alkylaminoethyl-1,1-bisphosphonates as inhibitors of trypanosoma cruzi farnesyl diphosphate synthase" . Journal of Medicinal Chemistry 55, no. 14 (2012) : 6445-6454.
http://dx.doi.org/10.1021/jm300425y
---------- MLA ----------
Aripirala, S., Szajnman, S.H., Jakoncic, J., Rodriguez, J.B., Docampo, R., Gabelli, S.B., et al. "Design, synthesis, calorimetry, and crystallographic analysis of 2-alkylaminoethyl-1,1-bisphosphonates as inhibitors of trypanosoma cruzi farnesyl diphosphate synthase" . Journal of Medicinal Chemistry, vol. 55, no. 14, 2012, pp. 6445-6454.
http://dx.doi.org/10.1021/jm300425y
---------- VANCOUVER ----------
Aripirala, S., Szajnman, S.H., Jakoncic, J., Rodriguez, J.B., Docampo, R., Gabelli, S.B., et al. Design, synthesis, calorimetry, and crystallographic analysis of 2-alkylaminoethyl-1,1-bisphosphonates as inhibitors of trypanosoma cruzi farnesyl diphosphate synthase. J. Med. Chem. 2012;55(14):6445-6454.
http://dx.doi.org/10.1021/jm300425y