Molecular Docking of Bacosides with Tryptophan Hydroxylase: A Model to Understand the Bacosides Mechanism

Abstract

Tryptophan hydroxylase (TPH) catalyses l-tryptophan into 5-hydroxy-l-tryptophan, which is the first and rate-limiting step of serotonin (5-HT) biosynthesis. Earlier, we found that TPH2 up-regulated in the hippocampus of postnatal rats after the oral treatment of Bacopa monniera leaf extract containing the active compound bacosides. However, the knowledge about the interactions between bacosides with TPH is limited. In this study, we take advantage of in silico approach to understand the interaction of bacoside-TPH complex using three different docking algorithms such as HexDock, PatchDock and AutoDock. All these three algorithms showed that bacoside A and A3 well fit into the cavity consists of active sites. Further, our analysis revealed that major active compounds bacoside A3 and A interact with different residues of TPH through hydrogen bond. Interestingly, Tyr235, Thr265 and Glu317 are the key residues among them, but none of them are either at tryptophan or BH4 binding region. However, its note worthy to mention that Tyr 235 is a catalytic sensitive residue, Thr265 is present in the flexible loop region and Glu317 is known to interacts with Fe. Interactions with these residues may critically regulate TPH function and thus serotonin synthesis. Our study suggested that the interaction of bacosides (A3/A) with TPH might up-regulate its activity to elevate the biosynthesis of 5-HT, thereby enhances learning and memory formation.

Alterations in Hippocampal Oxidative Stress, Expression of AMPA Receptor GluR2 Subunit and Associated Spatial Memory Loss by Bacopa monnieri Extract (CDRI-08) in Streptozotocin-Induced Diabetes Mellitus Type 2 Mice

“…As per recent evidence, Bacopa monnieri alcoholic extract has been reported to possesses neuroprotective action by reversing the memory impairment due to pilocarpine treatment in rats by up regulating the expression of the NMDA glutamate receptor GluN1 subunit in the hippocampus [ 75 ] and activity of the NMDA receptor in the cerebral cortex [ 76 ]. Also, it is likely that the CDRI-08modulates various neurotransmitters such as acetylcholine (ACh), serotonin, GABA, glutamate and dopamine in different brain regions that play role in enhancement of the cognitive functions [ 37 , 77 ]. A similar report has been published on effects of the curcumin, a known antioxidant, on the recovery of memory loss in rats by lowering the excitotoxicity by modulating the role of AMPA and NMDA glutamate receptors and thereby the synaptic plasticity in STZ-induced diabetic rats [ 22 ].…”

“…These include Bacosides A1–A3, Bacosides I–III and Bacosaponins A–G [ 36 ]. Recent studies have linked nootropic and neuroprotective role of Bacopa extract with its two major saponins- Bacosides A and B [ 29 , 37 ]. Ethanomedicine researchers have been keenly looking for the precise molecular mechanism underlying the action of its extract in recovery of the cognitive loss due to DM.…”

Molecular and Functional Characterization ofBacopa monniera: A Retrospective Review

“…This could be one of the mechanisms that enhance the learning and memory processing and it fits well into established concept in different models [ 66 , 67 ]. In addition to these studies, in silico analysis suggested that interaction of bacosides (A, A 3 ) with TPH2 possibly alters the activity of TPH2 that could be one of the mechanisms for increased 5-HT synthesis [ 68 ].…”

Bacoside A: Role in Cigarette Smoking Induced Changes in Brain

“…The observed lowering could be due to the downregulation of nAChR by BA. Apart from its ability to induce downregulation of nAChR expression, BA could have interacted with tyrosine hydroxylase [ 112 ] and modulated the release of catecholamines.…”