Effect of encapsulation in the anion receptor pocket of sub-domain IIA of human serum albumin on the modulation of pKa of warfarin and structurally similar acidic guests: A possible implication on biological activity

• Supramolecular and bio-supramolecular host induced pKa shift of WF and C343.
• Positive pKa shift with β-CD and the reverse with human serum albumin.
• Activity of prototropic-equilibrium-based drugs may be lost or enhanced with HSA.
• Properly functionalized drug with appropriate receptor pocket is very important.
• Encapsulation in HSA receptor pocket can lead to efficient drug delivery system.

Supramolecular and bio-supramolecular host assisted pKa shift of biologically relevant acidic guests, warfarin and coumarin 343, has been monitored using both steady-state and time resolved fluorescence spectroscopy. The anion receptors present in sub-domain IIA of human serum albumin (HSA) stabilize the anionic form of the guest and thereby shift pKa towards acidic range. On the other hand, the preferential binding of the neutral form of guests in the non-polar hydrophobic cavity of β-cyclodextrin results in up-shifted pKa. This shifting of pKa of drugs like warfarin, etc., whose therapeutic activity depends on the position of the acid–base equilibrium in human system, is of great importance in pharmacokinetics. The release of the active form of such drugs from macrocyclic carrier and subsequent distribution through the carrier protein should depend on the modulation of the overall pKa window brought about by the encapsulation in these hosts. Present work also suggests that properly optimized encapsulation in appropriate receptor pocket can enhance the bioavailability of drugs. This work also opens up the possibility to use HSA as encapsulator, instead of traditional cyclodextrins or other polymeric hosts, since such system may overcome toxicity as well as biocompatibility issues.

Figure optionsDownload as PowerPoint slide