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

Abstract

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

Experimental Correlation between Apparent pKa and Gelation Propensity in Amphiphilic Hydrogelators Derived from l-Dopa

“…Indeed, p K a may vary very much as a function of the tendency of the molecule to aggregate. For example, the apparent p K a of Fmoc-diphenylalanine (Fmoc-FF) results in two apparent p K a shifts of ∼6.4 and ∼2.2 pH units above the theoretical p K a (3.5), , as a result of the self-assembly process of the molecule into fibrils, consisting of antiparallel β-sheets, as reported by Saiani et al . To ascertain if our gelators have the same behavior, we made titration measurements in triplicate of basic solutions of the three molecules A , B and C , with concentration 0.5% w/v (which corresponds to 8.93 mM for A , 8.12 mM for B and 5.51 mM for C ) via the addition of aliquots of a 0.1 M HCl solution (Figure ).…”