Mechanistic Studies on the Stereoselectivity of the Serotonin 5‐HT_1A Receptor

Abstract

G-protein-coupled receptors (GPCRs) are involved in a wide range of physiological processes, and they have attracted considerable attention as important targets for developing new medicines. A central and largely unresolved question in drug discovery, which is especially relevant to GPCRs, concerns ligand selectivity: Why do certain molecules act as activators (agonists) whereas others, with nearly identical structures, act as blockers (antagonists) of GPCRs? To address this question, we employed all-atom, long-timescale molecular dynamics simulations to investigate how two diastereomers (epimers) of dihydrofuroaporphine bind to the serotonin 5-HT1A receptor and exert opposite effects. By using molecular interaction fingerprints, we discovered that the agonist could mobilize nearby amino acid residues to act as molecular switches for the formation of a continuous water channel. In contrast, the antagonist epimer remained firmly stabilized in the binding pocket.

The Molecular Mechanism of P2Y1 Receptor Activation

“…However, in both bound antagonists P2Y 1 R*-BPTU and P2Y 1 R-MRS2500, the conformation of Y324 7.53 did not change during the entire simulations. These results agree with previous findings [9] showing that Y324 7.53 plays a role as a switch, forming a continuous water channel during GPCR activation.…”

“…[6f, 9] In this work, we also observed distinct water channels inside the receptor (Figure S5). In antagonist-bound P2Y 1 R*-BPTU (Figure S5A,E), the extracellular ligand-binding pocket was filled with water molecules.…”

Intracellular passage of Na+in an active state g-protein coupled receptor

“…Such conservation of the Na + ion pocket and 302 the path for intracellular egress of Na + suggests that Na + transfer described in this study can 303 occur in all muscarinic receptors and other class A GPCRs, comprising a key "irreversible" 304 part of the activation mechanism. 305 306 307 binding site all the way to the cytoplasmic side of the receptor has previously also been 343 observed in simulations on the A 2A R and 5-HT 1A receptors (Yuan et al, 2014(Yuan et al, , 2016. We 344…”

Unravelling the Weak Interactions in Binary Clusters of Serotonin and Amino Acid Residues

“…On the other hand, owing to the arrangements of ethylamine side chain, serotonin could exist in alerted conformations, as discussed by rotational spectroscopy, which is highly interrelated to molecular recognition and intermolecular interactions. In particular, the ‐NH, ‐NH 2 group and ‐OH group all possess lone pair electrons and hydrogen atoms, enabling varied proton donor/acceptor sites on serotonin docking for different protein residues, causing altered X−H⋅⋅⋅Y hydrogen bonding interactions …”