title: Reversible human serum albumin binding of lipocrine: a circular dichroism study.
abstract: Lipocrine has been selected as an effective candidate for in vivo investigation because of its multiple biological properties, namely inhibition of AChE and BChE activities, inhibition of AChE-induced Aβ aggregation, and ability to protect cells against reactive oxygen species. To evaluate the possibility for lipocrine to become a lead and to be developed as a multipotent drug for the treatment of Alzheimer's disease, ADMET (absorption, distribution, metabolism, excretion, and toxicity) parameters need to be determined. Among ADMET parameters, distribution plays a key role in determining the lead drugability, and the drug binding to plasma proteins greatly influences the drug distribution. Here, the human serum albumin (HSA) binding of lipocrine has been studied by circular dichroism (CD) spectroscopy. The reversible binding of lipocrine is stereoselective as shown by the well-defined induced CD spectrum in its binding to HSA. The intensity of the CD signal changes upon changing the [drug]/[HSA] molar ratio, showing a different behavior for a [drug]/[HSA] up to 2/1 or over this molar ratio, suggesting a binding to multiple sites. Competition experiments show that lipocrine interacts significantly with all the main binding sites on the serum carrier. A direct competition has been monitored for site II and bilirubin-binding site, whereas a noncooperative binding should better describe the displacement observed at site I. Rac-lipocrine and its enantiomers are characterized by two different binding modes. Almost the same induced CD spectra were obtained for both (R)- and (S)-lipocrine complexed to HSA, suggesting a similar stereochemistry for the bound enantiomers.
authors.affiliation: Department of Pharmaceutical Sciences, University of Bologna, Bologna, Italy. carlo.bertucci@unibo.it
authors.forename: Carlo
authors.initials: C
authors.lastname: Bertucci
authors.forename: Angela
authors.initials: A
authors.lastname: De Simone
authors.forename: Marco
authors.initials: M
authors.lastname: Pistolozzi
authors.forename: Michela
authors.initials: M
authors.lastname: Rosini
mesh_terms: D001665:Binding Sites; D002851:Chromatography, High Pressure Liquid / Q000379:methods; D002942:Circular Dichroism / Q000379:methods*; D006801:Humans; D015394:Molecular Structure; D011485:Protein Binding; D012709:Serum Albumin / Q000737:chemistry / Q000378:metabolism*; D013619:Tacrine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000378:metabolism; D008063:Thioctic Acid / Q000031:analogs & derivatives* / Q000737:chemistry / Q000378:metabolism
chemical_list: D012709:Serum Albumin; C540521:lipocrine; D013619:Tacrine; D008063:Thioctic Acid