Publicação
Tackling solvation and permeability using computational methods
| Resumo: | Noncovalent interactions are essential for several biological processes, such as solvation and drug absorption. In this context, halogen bonds (XBs) are often overlooked despite their relevance in biological systems. Indeed, halogenation is a common strategy to improve drug pharmacokinetics, with many halogenated compounds in clinical use; however, the anisotropic nature of halogen is often not considered in in silico approaches. In this work, the impact of noncovalent interactions in solvation, with a special focus on XBs, was studied using two approaches: an implicit (faster) and an explicit solvent (more detailed) model. We provided optimized parameters, namely halogen PB radii (ropt), and validated the use of extra-points (EP), a simple strategy to account for the halogen anisotropy using empirical force fields, for MD simulations. This work showed that describing the halogen anisotropy is important even for the weakest XB donors, leading to an improvement of the calculated hydration free energies. Since desolvation plays an important role in protein-ligand systems, the use of optimized parameters was also assessed in the determination of binding free energies, with the description of halogen anisotropy in combination with ropt, achieving higher correlations with the experimental values. In the context of membrane permeability and noncovalent interactions, the literature is biased towards hydrogen bonds (HBs). To tackle this issue, the study of other noncovalent interactions was assessed for six currently used halogenated drugs, providing valuable insights about the use of EPs and the determination of the membrane permeability coefficients, showing that the use of this charge model does not impair the sampling of HBs. In addition, the synthesis of a library of structurally identical compounds was undertaken aiming to study the substituent effect on membrane permeability. The validation of a proper procedure to measure their permeability in Caco-2 cells is ongoing. |
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| Autores principais: | Fortuna, Andreia |
| Assunto: | Computational chemistry halogen bonds membrane permeability hydration free energies MD simulations Ligações não covalentes ligações de halogénio permeabilidade membranar energias livres de hidratação modelos de cargas |
| Ano: | 2024 |
| País: | Portugal |
| Tipo de documento: | tese de doutoramento |
| Tipo de acesso: | acesso embargado |
| Instituição associada: | Universidade de Lisboa |
| Idioma: | inglês |
| Origem: | Repositório da Universidade de Lisboa |
| Resumo: | Noncovalent interactions are essential for several biological processes, such as solvation and drug absorption. In this context, halogen bonds (XBs) are often overlooked despite their relevance in biological systems. Indeed, halogenation is a common strategy to improve drug pharmacokinetics, with many halogenated compounds in clinical use; however, the anisotropic nature of halogen is often not considered in in silico approaches. In this work, the impact of noncovalent interactions in solvation, with a special focus on XBs, was studied using two approaches: an implicit (faster) and an explicit solvent (more detailed) model. We provided optimized parameters, namely halogen PB radii (ropt), and validated the use of extra-points (EP), a simple strategy to account for the halogen anisotropy using empirical force fields, for MD simulations. This work showed that describing the halogen anisotropy is important even for the weakest XB donors, leading to an improvement of the calculated hydration free energies. Since desolvation plays an important role in protein-ligand systems, the use of optimized parameters was also assessed in the determination of binding free energies, with the description of halogen anisotropy in combination with ropt, achieving higher correlations with the experimental values. In the context of membrane permeability and noncovalent interactions, the literature is biased towards hydrogen bonds (HBs). To tackle this issue, the study of other noncovalent interactions was assessed for six currently used halogenated drugs, providing valuable insights about the use of EPs and the determination of the membrane permeability coefficients, showing that the use of this charge model does not impair the sampling of HBs. In addition, the synthesis of a library of structurally identical compounds was undertaken aiming to study the substituent effect on membrane permeability. The validation of a proper procedure to measure their permeability in Caco-2 cells is ongoing. |
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