title: Human serum albumin reduces the potency of acetylcholinesterase inhibitor based drugs for Alzheimer's disease.
abstract: Human serum albumin (HSA) induced modulation of acetylcholinesterase (AChE) inhibition activity of four well-known cholinergic inhibitors like tacrine hydrochloride (TAC), donepezil hydrochloride monohydrate (DON), (-) Huperzine A (HuPA), eserine (ESE) was monitored quantitatively by Ellman's method. Kinetic analysis of enzyme hydrolysis reaction revealed that while the mechanism of inhibition does not change significantly, the inhibition efficiency changes drastically in presence of HSA, particularly for DON and TAC. However, interestingly, no notable difference was observed in the cases of HuPA and/or ESE. For example, the IC50 value of AChE inhibition increases by almost 135% in presence of ∼250 μM HSA (IC50 = 159 ± 8 nM) while comparing with aqueous buffer solution of pH 8.0 (IC50 = 68 ± 4 nM) in DON. On the other hand, the change is almost insignificant (<10%) in case of HuPA under the similar condition. The experimentally observed difference in the extent of modulatory effect was correlated with the sequestration ability of HSA towards different drugs predicted from molecular docking calculations. The result in this study demonstrates the importance to consider the plasma protein binding tendency of a newly synthesized AD drug before claiming its potency over the existing one. Further, development of new and intelligent delivery medium that shields the administered drugs from serum adsorption may reduce the optimal drug dose requirement.
authors.affiliation: Center for Advanced Studies in Chemistry, North-Eastern Hill University, Shillong, 793 022, India.
authors.forename: Mullah Muhaiminul
authors.initials: MM
authors.lastname: Islam
authors.affiliation: Department of Biotechnology & Bio-informatics, North-Eastern Hill University, Shillong, 793 022, India.
authors.forename: Arun Bahadur
authors.initials: AB
authors.lastname: Gurung
authors.affiliation: Department of Biotechnology & Bio-informatics, North-Eastern Hill University, Shillong, 793 022, India.
authors.forename: Atanu
authors.initials: A
authors.lastname: Bhattacharjee
authors.affiliation: Department of Biotechnology & Bio-informatics, North-Eastern Hill University, Shillong, 793 022, India.
authors.forename: Kripamoy
authors.initials: K
authors.lastname: Aguan
authors.affiliation: Center for Advanced Studies in Chemistry, North-Eastern Hill University, Shillong, 793 022, India. Electronic address: smitra@nehu.ac.in.
authors.forename: Sivaprasad
authors.initials: S
authors.lastname: Mitra
mesh_terms: D000110:Acetylcholinesterase / Q000378:metabolism*; D000544:Alzheimer Disease / Q000188:drug therapy*; D002800:Cholinesterase Inhibitors / Q000494:pharmacology*; D006801:Humans; D007700:Kinetics; D062105:Molecular Docking Simulation / Q000379:methods; D012709:Serum Albumin / Q000378:metabolism*
chemical_list: D002800:Cholinesterase Inhibitors; D012709:Serum Albumin; D000110:Acetylcholinesterase
keywords: Acetylcholinesterase; Association constant; Drug sequestration; Enzyme kinetics; Human serum albumin; Inhibitor