title: Juliflorine: a potent natural peripheral anionic-site-binding inhibitor of acetylcholinesterase with calcium-channel blocking potential, a leading candidate for Alzheimer's disease therapy.
abstract: The alkaloid juliflorine (1) from Prosopis juliflora inhibited acetylcholinesterase (AChE, EC 3.1.1.7) and butyrylcholinesterase (BChE, EC 3.1.1.8) enzymes in a concentration-dependent fashion with IC50 values 0.42 and 0.12 microM, respectively. Lineweaver-Burk as well as Dixon plots and their secondary replots indicated that the nature of inhibition was purely of non-competitive type with Ki values 0.4 and 0.1 microM, against AChE and BChE, respectively. By molecular docking studies compound 1 was found to be ideally spaced inside the aromatic gorge of AChE with rings A/B remaining at the top and rings C/D penetrating deep into the gorge, that might be due to the greater hydrophobicity of rings C/D as compared to rings A/B, allowing their simultaneous interaction with the peripheral anionic and quaternary ammonium-binding sites. The 1-AChE complex was found to be stabilized by hydrophobic contacts, hydrogen bonding, and pi-pi stacking between the compound 1 and amino acid residues of the aromatic gorge of AChE. Amino acid residues Tyr70, Asp72, Tyr121, Trp279, and Tyr334 of the peripheral anionic site (PAS) of AChE were found to be exclusively involved in the hydrophobic contacts with compound 1 that might be responsible for the competitive mode of inhibition. Compound 1 also showed dose-dependent (30-500 microg/mL) spasmolytic and Ca2+-channel blocking activities in isolated rabbit jejunum preparations. The cholinesterase inhibitory potential along with calcium-channel blocking activity of compound 1 and safe profile in human neutrophils viable assay could make it a possible drug candidate for Alzheimer's disease.
authors: Dr. Panjwani Center for Molecular Medicine and Drug Research, International Center for Chemical Sciences, University of Karachi, Pakistan. hej@cyber.net.pk
authors: M Iqbal
authors: MI
authors: Choudhary
authors: Sarfraz Ahmad
authors: SA
authors: Nawaz
authors: Zaheer-ul-Haq
authors: M Kamran
authors: MK
authors: Azim
authors: M Nabeel
authors: MN
authors: Ghayur
authors: M Arif
authors: MA
authors: Lodhi
authors: Saima
authors: S
authors: Jalil
authors: Asaad
authors: A
authors: Khalid
authors: Amir
authors: A
authors: Ahmed
authors: Bernd M
authors: BM
authors: Rode
authors: Atta-ur-Rahman
authors: Anwar-ul-Hassan
authors: AU
authors: Gilani
authors: Viqar Uddin
authors: VU
authors: Ahmad
mesh_terms: D000470:Alkaloids / Q000494:pharmacology*; D000544:Alzheimer Disease / Q000188:drug therapy*; D000818:Animals; D001665:Binding Sites; D002118:Calcium / Q000378:metabolism; D015220:Calcium Channels / Q000378:metabolism*; D002800:Cholinesterase Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D006801:Humans; D006860:Hydrogen Bonding; D020128:Inhibitory Concentration 50; D007700:Kinetics; D008956:Models, Chemical; D008958:Models, Molecular; D008968:Molecular Conformation; D009504:Neutrophils / Q000378:metabolism; D011485:Protein Binding; D011487:Protein Conformation; D014101:Torpedo; D014443:Tyrosine / Q000737:chemistry
chemical_list: D000470:Alkaloids; D015220:Calcium Channels; D002800:Cholinesterase Inhibitors; D014443:Tyrosine; C048175:juliflorine; D002118:Calcium