RT Journal Article
T1 Controlling the selectivity of aminergic GPCR ligands from the extracellular vestibule
A1 Egyed, Attila
A1 Kelemen, Ádám A.
A1 Vass, Márton
A1 Visegrády, András
A1 Thee, Stephanie A.
A1 Wang, Zhiyong
A1 Graaf, Chris de
A1 Brea Floriani, José Manuel
A1 Loza García, María Isabel
A1 Leurs, Rob
A1 Keserű, György M.
K1 GPCR
K1 Selectivity
K1 Bitopic ligand
K1 Secondary binding pocket
K1 Fragment linking
AB In addition to the orthosteric binding pocket (OBP) of GPCRs, recent structural studies have revealed that there are several allosteric sites available for pharmacological intervention. The secondary binding pocket (SBP) of aminergic GPCRs is located in the extracellular vestibule of these receptors, and it has been suggested to be a potential selectivity pocket for bitopic ligands. Here, we applied a virtual screening protocol based on fragment docking to the SBP of the orthosteric ligand-receptor complex. This strategy was employed for a number of aminergic receptors. First, we designed dopamine D3 preferring bitopic compounds from a D2 selective orthosteric ligand. Next, we designed 5-HT2B selective bitopic compounds starting from the 5-HT1B preferring ergoline core of LSD. Comparing the serotonergic profiles of the new derivatives to that of LSD, we found that these derivatives became significantly biased towards the desired 5-HT2B receptor target. Finally, addressing the known limitations of H1 antihistamines, our protocol was successfully used to eliminate the well-known side effects related to the muscarinic M1 activity of amitriptyline while preserving H1 potency in some of the designed bitopic compounds. These applications highlight the usefulness of our new virtual screening protocol and offer a powerful strategy towards bitopic GPCR ligands with designed receptor profiles.
PB Elsevier
SN 0045-2068
YR 2021
FD 2021-03-19
LK https://hdl.handle.net/10347/45313
UL https://hdl.handle.net/10347/45313
LA eng
NO Egyed, A., Kelemen, Á A., Vass, M., Visegrády, A., Thee, S. A., Wang, Z., . . . Keserű, G. M. (2021). Controlling the selectivity of aminergic GPCR ligands from the extracellular vestibule. Bioorganic Chemistry, 111, 104832. doi:10.1016/j.bioorg.2021.104832
DS Minerva
RD 23 abr 2026