Elevated Fibrinogen Level Reduces Therapeutic Efficiency of AD Drugs: Biophysical Insights into the Interaction of FDA-Approved Cholinesterase Inhibitors with Human Fibrinogen

Abstract

Despite being the second most abundant protein in blood plasma, reports on the interaction of drugs with fibrinogen (FIB) are relatively scarce. The effect of FIB on the therapeutic potency of four FDAapproved Alzheimer's disease drugs, namely, tacrine (TAC), donepezil (DON), eserine (ESE), and huperzine (HUP), was investigated through a combination of different in vitro and in silico experiments. The efficiency of the drugs in inhibiting the activity of acetylcholinesterase (AChE) was significantly reduced in the presence of FIB. This effect was even found to be more substantial than that for the most abundant plasma protein, human serum albumin (HSA). For example, the relative change in IC 50 for TAC was found to be 65% in 10 μM FIB as opposed to 43% in the presence of 250 μM HSA. The relative trend of modulation in AChE activity showed consistency with the binding efficiency of the drugs and FIB. The sequestration of drugs in FIB, therefore reducing the availability of free drugs in solution, was identified to be the primary cause for the decrease in the AChE inhibition potency. This study aims to establish FIB as a vital component, while considering the therapeutic effectiveness of different newly developed AChE inhibitors.

Therapeutic opportunities of surface-active ionic liquids: a case study on acetylcholinesterase, citrate synthase and HeLa cell lines

“…AChE activity was measured by a protocol based on Ellman's method, 46 the details of which are described elsewhere. 47,48 In brief, acetylthiocholine iodide (ATChI) was used as the substrate and 5,5 0 -dithio-bis-2-nitrobenzoic acid (DTNB) was the colorimetric agent that produces 5-thio-2-nitrobenzoate, a yellowcoloured species that can be observed spectrophotometrically by measurement of absorbance at 412 nm, on reaction with ATChI. In both the enzymatic and non-enzymatic reactions, the concentration of DTNB was fixed at B317 mM.…”