title: In Silico and In Vitro Analysis of Bacoside A Aglycones and Its Derivatives as the Constituents Responsible for the Cognitive Effects of Bacopa monnieri.
abstract: Bacopa monnieri has been used in Ayurvedic medicine to improve memory and cognition. The active constituent responsible for its pharmacological effects is bacoside A, a mixture of dammarane-type triterpenoid saponins containing sugar chains linked to a steroid aglycone skeleton. Triterpenoid saponins have been reported to be transformed in vivo to metabolites that give better biological activity and pharmacokinetic characteristics. Thus, the activities of the parent compounds (bacosides), aglycones (jujubogenin and pseudojujubogenin) and their derivatives (ebelin lactone and bacogenin A1) were compared using a combination of in silico and in vitro screening methods. The compounds were docked into 5-HT1A, 5-HT2A, D1, D2, M1 receptors and acetylcholinesterase (AChE) using AutoDock and their central nervous system (CNS) drug-like properties were determined using Discovery Studio molecular properties and ADMET descriptors. The compounds were screened in vitro using radioligand receptor binding and AChE inhibition assays. In silico studies showed that the parent bacosides were not able to dock into the chosen CNS targets and had poor molecular properties as a CNS drug. In contrast, the aglycones and their derivatives showed better binding affinity and good CNS drug-like properties, were well absorbed through the intestines and had good blood brain barrier (BBB) penetration. Among the compounds tested in vitro, ebelin lactone showed binding affinity towards M1 (Ki = 0.45 μM) and 5-HT2A (4.21 μM) receptors. Bacoside A and bacopaside X (9.06 μM) showed binding affinity towards the D1 receptor. None of the compounds showed any inhibitory activity against AChE. Since the stimulation of M1 and 5-HT2A receptors has been implicated in memory and cognition and ebelin lactone was shown to have the strongest binding energy, highest BBB penetration and binding affinity towards M1 and 5-HT2A receptors, we suggest that B. monnieri constituents may be transformed in vivo to the active form before exerting their pharmacological activity.
authors.affiliation: Department of Pharmacy, Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia.
authors.forename: Seetha
authors.initials: S
authors.lastname: Ramasamy
authors.affiliation: Department of Pharmacy, Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia.
authors.forename: Sek Peng
authors.initials: SP
authors.lastname: Chin
authors.affiliation: Department of Pharmacy, Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia.
authors.forename: Sri Devi
authors.initials: SD
authors.lastname: Sukumaran
authors.affiliation: Department of Pharmacy, Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia.
authors.forename: Michael James Christopher
authors.initials: MJ
authors.lastname: Buckle
authors.affiliation: Department of Pharmacology, Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia.
authors.forename: Lik Voon
authors.initials: LV
authors.lastname: Kiew
authors.affiliation: Department of Pharmacy, Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia; Center for Natural Products and Drug Research (CENAR), University of Malaya, Kuala Lumpur, Malaysia.
authors.forename: Lip Yong
authors.initials: LY
authors.lastname: Chung
mesh_terms: D034681:Bacopa / Q000737:chemistry; D002490:Central Nervous System / Q000737:chemistry / Q000187:drug effects; D003071:Cognition / Q000187:drug effects / Q000502:physiology; D003072:Cognition Disorders / Q000188:drug therapy* / Q000473:pathology; D015928:Cognitive Behavioral Therapy; D003198:Computer Simulation; D006801:Humans; D008515:Medicine, Ayurvedic; D062105:Molecular Docking Simulation; D043643:Receptor, Muscarinic M1 / Q000737:chemistry; D044402:Receptor, Serotonin, 5-HT2A / Q000737:chemistry; D012503:Saponins / Q000737:chemistry* / Q000493:pharmacokinetics / Q000627:therapeutic use; D014315:Triterpenes / Q000737:chemistry* / Q000493:pharmacokinetics / Q000627:therapeutic use; D000097669:Dammaranes
chemical_list: D043643:Receptor, Muscarinic M1; D044402:Receptor, Serotonin, 5-HT2A; D012503:Saponins; D014315:Triterpenes; D000097669:Dammaranes; C500175:bacoside A; C400159:jujubogenin