Toward Refined Theoretical Models for the Description of Lipophilicity in Biomolecules
[eng] Lipophilicity is a key physicochemical descriptor used to understand the biological profile of (bio)organic compounds, xenobiotics and a broad variety of biochemical, pharmacological, and toxicological processes. This property is estimated from the partition coefficient between aqueous and non...
| Autor: | |
|---|---|
| Tipo de recurso: | tesis doctoral |
| Estado: | Versión publicada |
| Fecha de publicación: | 2019 |
| País: | España |
| Institución: | Universidad de Barcelona |
| Repositorio: | Dipòsit Digital de la UB |
| OAI Identifier: | oai:diposit.ub.edu:2445/129443 |
| Acceso en línea: | https://hdl.handle.net/2445/129443 http://hdl.handle.net/10803/666014 |
| Access Level: | acceso abierto |
| Palabra clave: | Bioquímica Farmacologia Biochemistry Pharmacology |
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Toward Refined Theoretical Models for the Description of Lipophilicity in Biomolecules |
| title |
Toward Refined Theoretical Models for the Description of Lipophilicity in Biomolecules |
| spellingShingle |
Toward Refined Theoretical Models for the Description of Lipophilicity in Biomolecules Zamora Ramírez, William J. Bioquímica Farmacologia Biochemistry Pharmacology |
| title_short |
Toward Refined Theoretical Models for the Description of Lipophilicity in Biomolecules |
| title_full |
Toward Refined Theoretical Models for the Description of Lipophilicity in Biomolecules |
| title_fullStr |
Toward Refined Theoretical Models for the Description of Lipophilicity in Biomolecules |
| title_full_unstemmed |
Toward Refined Theoretical Models for the Description of Lipophilicity in Biomolecules |
| title_sort |
Toward Refined Theoretical Models for the Description of Lipophilicity in Biomolecules |
| dc.creator.none.fl_str_mv |
Zamora Ramírez, William J. |
| author |
Zamora Ramírez, William J. |
| author_facet |
Zamora Ramírez, William J. |
| author_role |
author |
| dc.contributor.none.fl_str_mv |
Luque Garriga, F. Xavier Campanera Alsina, Josep Maria Universitat de Barcelona. Facultat de Farmàcia i Ciències de l'Alimentació |
| dc.subject.none.fl_str_mv |
Bioquímica Farmacologia Biochemistry Pharmacology |
| topic |
Bioquímica Farmacologia Biochemistry Pharmacology |
| description |
[eng] Lipophilicity is a key physicochemical descriptor used to understand the biological profile of (bio)organic compounds, xenobiotics and a broad variety of biochemical, pharmacological, and toxicological processes. This property is estimated from the partition coefficient between aqueous and nonaqueous environments for neutral compounds (PN) and corrected for the pH- dependence of ionizable compounds as the distribution coefficient (D). In this context, in this doctoral thesis the Miertus–Scrocco–Tomasi continuum solvation model was used to check the suitability of some reported and proposed formalisms to estimate the distribution coefficient for a set of small acidic and basic compounds. The results indicate that in general the simple pH- dependence model of the ionizable compound in water suffices to predict the partitioning at or around physiological pH. However, at extreme pH values, where ionic species are predominant, more elaborate models provide a better prediction of pH-dependent distribution curves of log D for both acidic and basic compounds as well as for amino acid analogues. New theoretical treatments for the lipophilicity profile of ionizable compounds were proposed to account for the electroneutrality in the phases of the n-octanol/water system. In this context, was used the theory of ion-transfer across the interface between two immiscible electrolyte solutions (ITIES). Experimental research is being carried out to see the scope of those formalisms developed in this thesis. Taking advantage of the successful results in small compounds, a lipophilicity scale adapted to different pH conditions was built for the 20 natural amino. The environment-dependence was introduced from the Dunbrack’s backbone- dependent conformational library using two weighting schemes for the rotamers: solvent-like (SolvL) and protein-like (ProtL) lipophilic schemes. The veracity of our scale was corroborated with successful correlations with other consolidated experimental scales. Characterization of short disordered peptides (retention times in RP-HPLC, log PN and log D7.4 values) was best described using the former approach, and biological properties of peptides with available three-dimensional structure (local context-dependent lipophilicity e.g binding free energies) with the second one. Our theoretical lipophilicity scale was thus characterized by its versatility and adaptability, which confers a unifying character. Future studies will address the application of this methodology to the calculation of lipophilic parameters for no proteogenic amino acids, other conformations of the actual residues (proline cis) and other fragments relevant to proteins. On the other hand, the applicability of the present versatile scale is vast and promising, including for instance the use as scorings for protein- protein docking protocols, among others. |
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2019 |
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2019 |
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info:eu-repo/semantics/doctoralThesis info:eu-repo/semantics/publishedVersion |
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doctoralThesis |
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publishedVersion |
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https://hdl.handle.net/2445/129443 http://hdl.handle.net/10803/666014 |
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https://hdl.handle.net/2445/129443 http://hdl.handle.net/10803/666014 |
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Inglés |
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Inglés |
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(c) Zamora, 2019 info:eu-repo/semantics/openAccess |
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(c) Zamora, 2019 |
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openAccess |
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application/pdf |
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Universitat de Barcelona |
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Universitat de Barcelona |
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Tesis Doctorals - Facultat - Farmàcia i Ciències de l'Alimentació reponame:Dipòsit Digital de la UB instname:Universidad de Barcelona |
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Universidad de Barcelona |
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Dipòsit Digital de la UB |
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Dipòsit Digital de la UB |
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1869417998973927424 |
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Toward Refined Theoretical Models for the Description of Lipophilicity in BiomoleculesZamora Ramírez, William J.BioquímicaFarmacologiaBiochemistryPharmacology[eng] Lipophilicity is a key physicochemical descriptor used to understand the biological profile of (bio)organic compounds, xenobiotics and a broad variety of biochemical, pharmacological, and toxicological processes. This property is estimated from the partition coefficient between aqueous and nonaqueous environments for neutral compounds (PN) and corrected for the pH- dependence of ionizable compounds as the distribution coefficient (D). In this context, in this doctoral thesis the Miertus–Scrocco–Tomasi continuum solvation model was used to check the suitability of some reported and proposed formalisms to estimate the distribution coefficient for a set of small acidic and basic compounds. The results indicate that in general the simple pH- dependence model of the ionizable compound in water suffices to predict the partitioning at or around physiological pH. However, at extreme pH values, where ionic species are predominant, more elaborate models provide a better prediction of pH-dependent distribution curves of log D for both acidic and basic compounds as well as for amino acid analogues. New theoretical treatments for the lipophilicity profile of ionizable compounds were proposed to account for the electroneutrality in the phases of the n-octanol/water system. In this context, was used the theory of ion-transfer across the interface between two immiscible electrolyte solutions (ITIES). Experimental research is being carried out to see the scope of those formalisms developed in this thesis. Taking advantage of the successful results in small compounds, a lipophilicity scale adapted to different pH conditions was built for the 20 natural amino. The environment-dependence was introduced from the Dunbrack’s backbone- dependent conformational library using two weighting schemes for the rotamers: solvent-like (SolvL) and protein-like (ProtL) lipophilic schemes. The veracity of our scale was corroborated with successful correlations with other consolidated experimental scales. Characterization of short disordered peptides (retention times in RP-HPLC, log PN and log D7.4 values) was best described using the former approach, and biological properties of peptides with available three-dimensional structure (local context-dependent lipophilicity e.g binding free energies) with the second one. Our theoretical lipophilicity scale was thus characterized by its versatility and adaptability, which confers a unifying character. Future studies will address the application of this methodology to the calculation of lipophilic parameters for no proteogenic amino acids, other conformations of the actual residues (proline cis) and other fragments relevant to proteins. On the other hand, the applicability of the present versatile scale is vast and promising, including for instance the use as scorings for protein- protein docking protocols, among others.[spa] La lipofilicidad es un descriptor fisicoquímico clave utilizado para comprender el perfil biológico de los compuestos (bio)orgánicos, xenobióticos y una amplia variedad de procesos bioquímicos, farmacológicos y toxicológicos. Esta propiedad se estima a partir del coeficiente de reparto entre ambientes acuosos y no acuosos para compuestos neutros (PN) y corregido para la dependencia del pH de los compuestos ionizables como el coeficiente de distribución (D). En este contexto, en esta tesis doctoral se usó el modelo de solvatación continua de Miertus-Scrocco-Tomasi para verificar la idoneidad de algunos formalismos reportados y propuestos para estimar el coeficiente de distribución para un conjunto de pequeños compuestos ácidos y básicos. Los resultados indican que, en general, el modelo simple de dependencia del pH del compuesto ionizable en agua es suficiente para predecir la partición en o alrededor del pH fisiológico. Sin embargo, a valores extremos de pH, donde predominan las especies iónicas, los modelos más elaborados proporcionan una mejor predicción de las curvas de distribución dependientes del pH del log D, tanto para compuestos ácidos como básicos, así como para análogos de aminoácidos. Se propusieron nuevos tratamientos teóricos para el perfil de lipofilicidad de compuestos ionizables para explicar la electroneutralidad en las fases del sistema n-octanol/agua. En este contexto, se utilizó la teoría de la transferencia de iones a través de la interfase entre dos disoluciones de electrólitos inmiscibles (ITIES por sus siglas en inglés). Se están llevando a cabo investigaciones experimentales para ver el alcance de los formalismos desarrollados en esta tesis. Aprovechando los resultados exitosos en pequeños compuestos, se construyó una escala de lipofilicidad adaptada a diferentes condiciones de pH para los 20 aminoácidos naturales. La dependencia del entorno se introdujo a partir de la biblioteca conformacional dependiente del “backbone” de Dunbrack utilizando dos esquemas de ponderación para los rotámeros: el esquema lipofílico tipo solvente (SolvL) y tipo proteíco (ProtL). La veracidad de nuestra escala se corroboró con correlaciones exitosas con otras escalas experimentales ya consolidadas. La caracterización de péptidos cortos desordenados (valores de tiempos de retención en “RP-HPLC”, log PN y log D7.4) fue mejor descrita utilizando el primer esquema, y las propiedades biológicas de los péptidos con estructura tridimensional disponible (lipofilicidad dependiente del contexto local y energías libres de unión) con la segunda. Nuestra escala teórica de lipofilicidad se caracterizó por su versatilidad y adaptabilidad, lo que le confiere un carácter unificador. Los estudios futuros abordarán la aplicación de esta metodología al cálculo de parámetros lipofilicos para aminoácidos no proteogénicos, otras conformaciones de los residuos actuales (prolina cis) y otros fragmentos relevantes para las proteínas. Por otro lado, la aplicabilidad de la escala versátil actual es amplia y prometedora, incluyendo, por ejemplo, el uso como ponderantes para protocolos de acoplamiento de proteína-proteína, entre otros.Universitat de BarcelonaLuque Garriga, F. XavierCampanera Alsina, Josep MariaUniversitat de Barcelona. Facultat de Farmàcia i Ciències de l'Alimentació2019info:eu-repo/semantics/doctoralThesisinfo:eu-repo/semantics/publishedVersionapplication/pdfhttps://hdl.handle.net/2445/129443http://hdl.handle.net/10803/666014Tesis Doctorals - Facultat - Farmàcia i Ciències de l'Alimentacióreponame:Dipòsit Digital de la UBinstname:Universidad de BarcelonaInglés(c) Zamora, 2019info:eu-repo/semantics/openAccessoai:diposit.ub.edu:2445/1294432026-05-27T06:46:51Z |
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