Potential binding modes of the gut bacterial metabolite, 5-hydroxyindole, to the intestinal L-type calcium channels and its impact on the microbiota in rats

Abstract

Intestinal microbiota and microbiota-derived metabolites play a key role in regulating the host physiology. Recently, we have identified a gut-bacterial metabolite, namely 5-hydroxyindole, as a potent stimulant of intestinal motility via its modulation of L-type voltage-gated calcium channels located on the intestinal smooth muscle cells. Dysregulation of L-type voltage-gated calcium channels is associated with various gastrointestinal motility disorders, including constipation, making L-type voltage-gated calcium channels an important target for drug development. Nonetheless, the majority of currently available drugs are associated with alteration of the gut microbiota. Using 16S rRNA sequencing this study shows that, when administered orally, 5-hydroxyindole has only marginal effects on the rat cecal microbiota. Molecular dynamics simulations propose potential-binding pockets of 5-hydroxyindole in the α1 subunit of the L-type voltage-gated calcium channels and when its stimulatory effect on the rat colonic contractility was compared to 16 different analogues, ex-vivo , 5-hydroxyindole stood as the most potent enhancer of the intestinal contractility. Overall, the present findings imply a potential role of microbiota-derived metabolites as candidate therapeutics for targeted treatment of slow intestinal motility-related disorders including constipation.

Exploring the Ligand Binding and Conformational Dynamics of the Substrate-Binding Domain 1 of the ABC Transporter GlnPQ

“…To further characterize the differences in the affinity of the ligands of SBD1, we performed coarse-grained molecular dynamics (CG MD) simulations using the Martini 3 force field , in combination with the Go̅-like model on the newly resolved crystallographic structure of SBD1 (PDB ID: 8B5E). The use of the CG Martini model in combination with Go̅-like interactions allows to sample long time scale protein dynamics, including spontaneous binding of ligands, as demonstrated previously. − …”

Broccoli-Derived Exosome-like Nanoparticles Alleviate Loperamide-Induced Constipation, in Correlation with Regulation on Gut Microbiota and Tryptophan Metabolism

“…Tryptophan, a typical aromatic amino acid, plays a crucial role in the maintenance of immune homeostasis and gut microbiota . The microbial metabolites of tryptophan, such as 5-hydroxytryptamine, 5-hydroxyindole, and 5-HT 2B receptors, can stimulate the smooth muscle contraction in the colon, mediate secretion of intestinal fluid, and electrolytes, or promote the cholinergic pathways to accelerate colonic transit in mice with constipation. ,, In the gut, the microbiota directly or indirectly affects the tryptophan metabolic pathways, including the kynurenine metabolic pathway, 5-hydroxytryptamine metabolic pathway, and indole derivative metabolic pathway, which are highly correlated to intestinal motility and constipation. , Here, interestingly, BENs significantly increased LOP-lowered tryptophan metabolites 3-indoleacetic acid and indole-3-pyruvic acid in mice with constipation, and this might be correlated to BEN-induced alterations in the gut microbial composition, as evidenced by the Pearson-based correlation network.…”

Pragmatic Coarse-Graining of Proteins: Models and Applications

“…242 Recent studies used the speed-up of Martini to decipher the binding of ligands to glycine receptors, 243 energy-coupling factor transporters, 244 and an L-type voltage-gated calcium channel. 245 Furthermore, Martini has been integrated into the HADDOCK workflow for protein−protein 246 and protein−DNA docking, 247 speeding up the docking of biomolecular complexes by around one order of magnitude compared to AA models.…”

“…Martini has been shown to predict protein–ligand binding and dissociation pathways with high accuracy using unbiased millisecond long simulations (Figure , f), achieving performance 110–350× faster than AA simulations . Recent studies used the speed-up of Martini to decipher the binding of ligands to glycine receptors, energy-coupling factor transporters, and an L-type voltage-gated calcium channel . Furthermore, Martini has been integrated into the HADDOCK workflow for protein–protein and protein–DNA docking, speeding up the docking of biomolecular complexes by around one order of magnitude compared to AA models.…”