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.

Differential inhibition of human erythrocyte acetylcholinesterase by polyphenols epigallocatechin‐3‐gallate and resveratrol. Relevance of the membrane‐bound form

“…Although in this work EGCG induced only a moderate inhibition of AChE‐E, membrane binding arises as an important parameter to take into account. Indeed, a number of papers describing new inhibitors use the soluble commercial form of the enzyme . This approach may underestimate the activity of some potential inhibitors since physiological relevant variants of AChE are associated with cell membranes.…”

Elucidation of molecular mechanism(s) of cognition enhancing activity of Bacomind®: A standardized extract of bacopa monnieri

“…Moreover, the metabolites of various Bacopa constituents could also be modulating these molecular targets for its memory enhancing activity as reported recently. [ 32 ]…”

Bacopa monnieri and Their Bioactive Compounds Inferred Multi-Target Treatment Strategy for Neurological Diseases: A Cheminformatics and System Pharmacology Approach

“…B. monnieri contains alkaloid brahmine, nicotinine, herpestine, bacosides A and B, saponins A, B and C, triterpenoid saponins, stigmastanol, β-sitosterol, betulinic acid, D-mannitol, stigmasterol, α-alanine, aspartic acid, glutamic acid, and serine and pseudojujubogenin glycoside [7]. The plant possesses a wide variety of pharmacologically active principles including memory enhancing, tranquillizing, sedative, antidepressant, antioxidant, cognitive, anticancer, antianxiety, adaptogenic, antiepileptic, gastrointestinal effects, endocrine, gastrointestinal, smooth muscle relaxant effects, cardiovascular, analgesic, antipyretic, antidiabetic, antiarthritic, anticancer, antihypertensive, antimicrobial, antilipidemia, anti-inflammatory, neuroprotective, and hepatoprotective activities [8][9][10].…”

“…Diverse mechanisms of action for its cognitive effects have been proposed, including acetylcholinesterase (AChE) inhibition, antioxidant neuroprotection, β-amyloid reduction, neurotransmitter modulation (acetylcholine [ACh], 5-hydroxytryptamine , dopamine [DA]), choline acetyltransferase activation, and increased cerebral blood flow [12]. Theoretically, paring B. monnieri with a stimulant would ward off malaise, but this combination has not been tested [10]. Metabolites or active compounds from B. monnieri interact with the dopamine and serotonergic systems, but its main molecular mechanism concerns promoting neuron communication.…”