posted on 2020-02-11, 11:29authored byGergő Dargó, Dávid Bajusz, Kristóf Simon, Judit Müller, György T. Balogh
The knowledge on human serum albumin
(HSA) binding is of utmost
importance as it affects pharmacokinetic behavior and bioavailability
of drugs. In this article, we report a novel method to screen for
ionizable molecules with high HSA binding affinity based on pKa shifts using UV-pH titration. We investigated
the HSA binding of 27 drugs and compared the results to experimental
data from conventional methods. In most cases, significant shifts
(ΔpKa > 0.1) were observed for
drugs
with high HSA binding, while no change could be detected for low-affinity
binders. We showed the pivotal role of ionization centers in the formation
of strong interactions between drug and HSA using molecular docking
studies. We also verified our findings by testing five modified analogues
designed by structural considerations. Significant decreases in their
HSA binding proved that the UV-pH titration method combined with an
in silico support can be used as a medicinal chemistry tool to assist
rational molecular design.