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Critical Assessment of pH-Dependent Lipophilicity Profiles of Small Molecules: Which One Should We Use and In Which Cases?
Bertsch, Esteban; Suñer, Sebastián; Pinheiro, Silvana; Zamora, William J.
Afiliação
  • Bertsch E; CBio3 Laboratory, School of Chemistry, University of Costa Rica, San Pedro, San José, Costa Rica.
  • Suñer S; CBio3 Laboratory, School of Chemistry, University of Costa Rica, San Pedro, San José, Costa Rica.
  • Pinheiro S; CBio3 Laboratory, School of Chemistry, University of Costa Rica, San Pedro, San José, Costa Rica.
  • Zamora WJ; Laboratory of Computational Toxicology and Artificial Intelligence (LaToxCIA), Biological Testing Laboratory (LEBi), University of Costa Rica, San Pedro, San José, Costa Rica.
Chemphyschem ; 24(24): e202300548, 2023 Dec 14.
Article em En | MEDLINE | ID: mdl-37788220
Lipophilicity is a physicochemical property with wide relevance in drug design, computational biology, food, environmental and medicinal chemistry. Lipophilicity is commonly expressed as the partition coefficient for neutral molecules, whereas for molecules with ionizable groups, the distribution coefficient (D) at a given pH is used. The logDpH is usually predicted using a pH correction over the logPN using the pKa of ionizable molecules, while often ignoring the apparent ion pair partitioning ( P IP app ) ${{\rm{(}}P_{{\rm{IP}}}^{{\rm{app}}} )}$ . In this work, we studied the impact of ( P IP app ) ${{\rm{(}}P_{{\rm{IP}}}^{{\rm{app}}} )}$ on the prediction of both the experimental lipophilicity of small molecules and experimental lipophilicity-based applications and metrics such as lipophilic efficiency (LipE), distribution of spiked drugs in milk products, and pH-dependent partition of water contaminants in synthetic passive samples such as silicones. Our findings show that better predictions are obtained by considering the apparent ion pair partitioning. In this context, we developed machine learning algorithms to determine the cases that P I app ${P_{\rm{I}}^{{\rm{app}}} }$ should be considered. The results indicate that small, rigid, and unsaturated molecules with logPN close to zero, which present a significant proportion of ionic species in the aqueous phase, were better modeled using the apparent ion pair partitioning ( P IP app ) ${{\rm{(}}P_{{\rm{IP}}}^{{\rm{app}}} )}$ . Finally, our findings can serve as guidance to the scientific community working in early-stage drug design, food, and environmental chemistry.
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Tipo de estudo: Prognostic_studies Idioma: En Revista: Chemphyschem Assunto da revista: BIOFISICA / QUIMICA Ano de publicação: 2023 Tipo de documento: Article País de afiliação: Costa Rica País de publicação: Alemanha

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Tipo de estudo: Prognostic_studies Idioma: En Revista: Chemphyschem Assunto da revista: BIOFISICA / QUIMICA Ano de publicação: 2023 Tipo de documento: Article País de afiliação: Costa Rica País de publicação: Alemanha