title: Prenylated xanthones from mangosteen as promising cholinesterase inhibitors and their molecular docking studies.
abstract: Garcinia mangostana is a well-known tropical plant found mostly in South East Asia. The present study investigated acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) inhibitory activities of G. mangostana extract and its chemical constituents using Ellman's colorimetric method. Cholinesterase inhibitory-guided approach led to identification of six bioactive prenylated xanthones showing moderate to potent cholinesterases inhibition with IC50 values of lower than 20.5 μM. The most potent inhibitor of AChE was garcinone C while γ-mangostin was the most potent inhibitor of BChE with IC50 values of 1.24 and 1.78 μM, respectively. Among the xanthones, mangostanol, 3-isomangostin, garcinone C and α-mangostin are AChE selective inhibitors, 8-deoxygartanin is a BChE selective inhibitor while γ-mangostin is a dual inhibitor. Preliminary structure-activity relationship suggests the importance of the C-8 prenyl and C-7 hydroxy groups for good AChE and BChE inhibitory activities. The enzyme kinetic studies indicate that both α-mangostin and garcinone C are mixed-mode inhibitors, while γ-mangostin is a non-competitive inhibitor of AChE. In contrast, both γ-mangostin and garcinone C are uncompetitive inhibitors, while α-mangostin is a mixed-mode inhibitor of BChE. Molecular docking studies revealed that α-mangostin, γ-mangostin and garcinone C interacts differently with the five important regions of AChE and BChE. The nature of protein-ligand interactions is mainly hydrophobic and hydrogen bonding. These bioactive prenylated xanthones are worthy for further investigations.
authors.affiliation: Discipline of Pharmacology, School of Pharmaceutical Sciences, Universiti Sains Malaysia, 11800 Penang, Malaysia.
authors.forename: K Y
authors.initials: KY
authors.lastname: Khaw
authors.affiliation: Bioprocess Division, School of Industrial Technology, Universiti Sains Malaysia, 11800 Penang, Malaysia.
authors.forename: S B
authors.initials: SB
authors.lastname: Choi
authors.affiliation: Institute for Research in Molecular Medicine (INFORMM), Universiti Sains Malaysia, 11800 Penang, Malaysia.
authors.forename: S C
authors.initials: SC
authors.lastname: Tan
authors.affiliation: Pharmaceutical Design and Simulation (PhDS) Laboratory, School of Pharmaceutical Sciences, Universiti Sains Malaysia, 11800 Penang, Malaysia.
authors.forename: H A
authors.initials: HA
authors.lastname: Wahab
authors.affiliation: Discipline of Pharmaceutical Chemistry, School of Pharmaceutical Sciences, Universiti Sains Malaysia, 11800 Penang, Malaysia.
authors.forename: K L
authors.initials: KL
authors.lastname: Chan
authors.affiliation: Discipline of Pharmacology, School of Pharmaceutical Sciences, Universiti Sains Malaysia, 11800 Penang, Malaysia. Electronic address: vicky@usm.my.
authors.forename: V
authors.initials: V
authors.lastname: Murugaiyah
mesh_terms: D002800:Cholinesterase Inhibitors / Q000494:pharmacology*; D029762:Garcinia mangostana / Q000737:chemistry*; D062105:Molecular Docking Simulation; D015394:Molecular Structure; D054876:Prenylation; D013329:Structure-Activity Relationship; D044004:Xanthones / Q000494:pharmacology*
chemical_list: C114655:3-isomangostin; C000596093:8-deoxygartanin; D002800:Cholinesterase Inhibitors; D044004:Xanthones; C000596092:garcinone C; C021053:mangostin
keywords: Acetylcholinesterase; Butyrylcholinesterase; Garcinone C; Molecular docking; α-Mangostin; γ-Mangostin