Structural determinants of the neuronal glycine transporter 2 for the selective inhibitors ALX1393 and ORG25543
EntityUAM. Departamento de Biología Molecular
PublisherAmerican Chemical Society
10.1021/acschemneuro.0c00602ACS Chemical Neuroscience 12.11 (2021): 1860-1872
Funded byThis work was supported by grants of the Spanish ‘Ministerio de Economía y Competitividad’, grant number SAF2017-84235-R (AEI/FEDER, EU) to B.L.-C. and by institutional grants from the Fundación Ramón Areces and Banco de Santander to the CBMSO
ProjectGobierno de España. SAF2017-84235-R
SubjectsALX1393; ORG25543; Glycinergic neurotransmission; Inhibitor binding; Neuronal glycine transporter 2; Pain; Biología y Biomedicina / Biología
Rights© 2021 American Chemical Society
Esta obra está bajo una Licencia Creative Commons Atribución 4.0 Internacional.
The neuronal glycine transporter GlyT2 modulates inhibitory glycinergic neurotransmission by controlling the extracellular concentration of synaptic glycine and the supply of neurotransmitter to the presynaptic terminal. Spinal cord glycinergic neurons present in the dorsal horn diminish their activity in pathological pain conditions and behave as gate keepers of the touch-pain circuitry. The pharmacological blockade of GlyT2 reduces the progression of the painful signal to rostral areas of the central nervous system by increasing glycine extracellular levels, so it has analgesic action. O-[(2-benzyloxyphenyl-3-fluorophenyl)methyl]-L-serine (ALX1393) and N-[[1-(dimethylamino)cyclopentyl]methyl]-3,5-dimethoxy-4-(phenylmethoxy)benzamide (ORG25543) are two selective GlyT2 inhibitors with nanomolar affinity for the transporter and analgesic effects in pain animal models, although with deficiencies which preclude further clinical development. In this report, we performed a comparative ligand docking of ALX1393 and ORG25543 on a validated GlyT2 structural model including all ligand sites constructed by homology with the crystallized dopamine transporter from Drosophila melanogaster. Molecular dynamics simulations and energy analysis of the complex and functional analysis of a series of point mutants permitted to determine the structural determinants of ALX1393 and ORG25543 discrimination by GlyT2. The ligands establish simultaneous contacts with residues present in transmembrane domains 1, 3, 6, and 8 and block the transporter in outward-facing conformation and hence inhibit glycine transport. In addition, differential interactions of ALX1393 with the cation bound at Na1 site and ORG25543 with TM10 define the differential sites of the inhibitors and explain some of their individual features. Structural information about the interactions with GlyT2 may provide useful tools for new drug discovery
Google Scholar:Benito-Muñoz, Cristina - Perona, Almudena - Felipe, Raquel - Pérez-Siles, Gonzalo - Núñez, Enrique - Aragón, Carmen - López Corcuera, Beatriz
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