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Entalpia frente a la unión impulsada por la entropía de los bisfosfonatos a la farnesil difosfato sintasa
Fenglin Yin1, Rong Cao, Amanda Goddard
1Department of Biophysics, University of Illinois at Urbana-Champaign, 607 South Mathews Avenue, Urbana, Illinois 61801, USA.
Journal of the American Chemical Society
|March 16, 2006
Resumen
Hemos estudiado cómo seis bifosfonatos se unen a la farnesil difosfato sintasa (FPPS) utilizando calorimetría de titulación isotérmica. La unión es impulsada por entalpía para algunos compuestos y por entropía para otros, lo que influye en la inhibición de FPPS y el potencial desarrollo de fármacos.
Área de la Ciencia:
- La bioquímica es la bioquímica.
- La cinética de las enzimas.
- Descubrimiento de fármacos.
Sus antecedentes:
- La farnesil difosfato sintasa (FPPS) es una enzima clave en la biosíntesis de isoprenoides.
- Los bisfosfonatos son una clase de fármacos con importantes aplicaciones terapéuticas, incluyendo la inmunoterapia contra el cáncer y la quimioterapia antiparasitaria.
- Comprender los mecanismos de unión de los bifosfonatos al FPPS es crucial para desarrollar inhibidores más potentes y selectivos.
Objetivo del estudio:
- Para investigar los parámetros de unión termodinámica de seis bisfosfonatos para Trypanosoma brucei FPPS.
- Para correlacionar la termodinámica de unión con los datos de inhibición de enzimas.
- Para dilucidar la base molecular de las interacciones bisfosfonato-FPPS.
Principales métodos:
- Se empleó calorimetría de titulación isotérmica (ITC) para medir la unión de los bifosfonatos al FPPS.
- Se utilizaron ensayos radioquímicos para determinar las constantes de inhibición del FPPS.
- Los parámetros termodinámicos (ΔH, ΔS, ΔG) se calcularon a partir de los datos del ITC.
Principales resultados:
- Se encontró que la unión del bisfosfonato al FPPS es impulsada por entalpía o entropía, dependiendo del compuesto específico y el pH.
- La unión al zoledronato exhibió un cambio de entropía a entalpía al aumentar el pH de 7.4 a 8.5.
- La energía libre de enlace (ΔG) está fuertemente correlacionada con la inhibición del FPPS (R2 = 0,85).
Conclusiones:
- El modo de unión (entalpia versus entropía) está influenciado por las propiedades de la cadena lateral del bisfosfonato y el pH.
- Las cadenas laterales cargadas contribuyen a la unión impulsada por entalpía a través de la desolución y el aumento de la entropía del agua.
- La protonación de las cadenas laterales básicas en el sitio activo mejora la actividad de ciertos bifosfonatos, destacando su potencial como inhibidores del FPPS.
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