Critical Assessment of pH-Dependent Lipophilicity Profiles of Small Molecules: Which One Should We Use and In Which Cases?

Autor: Bertsch E; University of Costa Rica School of Chemistry, School of Chemistry, COSTA RICA., Suñer S; University of Costa Rica School of Chemistry, School of Chemistry, COSTA RICA., Pinheiro S; University of Costa Rica School of Chemistry, School of Chemistry, COSTA RICA., Zamora WJ; Universidad de Costa Rica, School of Chemistry - Faculty of Pharmacy - Graduate School UCR, San José,, 2060, San José, COSTA RICA.
Jazyk: angličtina
Zdroj: Chemphyschem : a European journal of chemical physics and physical chemistry [Chemphyschem] 2023 Oct 03, pp. e202300548. Date of Electronic Publication: 2023 Oct 03.
DOI: 10.1002/cphc.202300548
Abstrakt: Lipophilicity is a physicochemical property with wide relevance in drug design, computational biology, and 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, while often ignoring the apparent ionic partition [[EQUATION]]. In this work, we studied the impact of [[EQUATION]] 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 ionic partition. In this context, we developed machine learning algorithms to determine the cases that [[EQUATION]] 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 ionic partition [[EQUATION]]). Finally, our findings can serve as guidance to the scientific community working in early-stage drug design, food, and environmental chemistry.
(© 2023 Wiley-VCH GmbH.)
Databáze: MEDLINE
Externí odkaz: