Biorelevant pK(a) (37 °C) predicted from the 2D structure of the molecule and its pK(a) at 25 °C

Abstract

Values of the ionization constants at 37 °C, which are scarcely reported, are more meaningful for interpreting mechanisms of cellular transport by ionizable molecules and in mechanistic dissolution studies, which are often performed at the biorelevant temperature. An equation was developed where the pK(a) values of drug-like molecules determined at 25 °C can be simply converted to values at 37 °C, without additional measurement. The differences between the values, ΔpK(a)=pK(a)³⁷-pK(a)²⁵, were linearly fitted to a function of pK(a)²⁵ and the standard entropy of ionization, ΔS°, where the latter term was approximated by the five Abraham linear free energy solvation descriptors using multiple linear regression. The Abraham descriptors (H-bond donor and acceptor strengths, dipolar solute-solvent interactions potential, the pi- and n-electrons dispersion force, and molar volume) were determined from the 2-dimensional structure of the molecules. A total of 143 mostly drug-like molecules (207 pK(a) values at 25 °C and at 37 °C) were chosen for the study. The pK(a) values of many were determined here for the first time. Included were 34 weak acids, 85 weak bases, and 24 amphoteric compounds (6 ordinary ampholytes, 18 zwitterions).