RT Journal Article
T1 Allosteric modulation of dopamine D2L receptor in complex with Gi1 and Gi2 proteins: the effect of subtle structural and stereochemical ligand modifications
A1 Żuk, Justyna
A1 Bartuzi, Damian
A1 Silva, Andrea G.
A1 Pitucha, Monika
A1 Koszła, Oliwia
A1 Tomasz M. Wróbel, 
A1 Matosiuk, Dariusz
A1 Castro Pérez, María de los Ángeles
A1 Agnieszka A. Kaczor, 
K1 Dopamine D2 receptor
K1 GPCRs
K1 Molecular dynamics
K1 Molecular switches
K1 Negative allosteric modulators
K1 Positive allosteric modulators
AB Background: Allosteric modulation of G protein-coupled receptors (GPCRs) is nowadays one of the hot topics in drug discovery. In particular, allosteric modulators of D2 receptor have been proposed as potential modern therapeutics to treat schizophrenia and Parkinson’s disease. Methods: To address some subtle structural and stereochemical aspects of allosteric modulation of D2 receptor, we performed extensive in silico studies of both enantiomers of two compounds (compound 1 and compound 2), and one of them (compound 2) was synthesized as a racemate in-house and studied in vitro. Results: Our molecular dynamics simulations confirmed literature reports that the R enantiomer of compound 1 is a positive allosteric modulator of the D2L receptor, while its S enantiomer is a negative allosteric modulator. Moreover, based on the principal component analysis (PCA), we hypothesized that both enantiomers of compound 2 behave as silent allosteric modulators, in line with our in vitro studies. PCA calculations suggest that the most pronounced modulator-induced receptor rearrangements occur at the transmembrane helix 7 (TM7). In particular, TM7 bending at the conserved P7.50 and G7.42 was observed. The latter resides next to the Y7.43, which is a significant part of the orthosteric binding site. Moreover, the W7.40 conformation seems to be affected by the presence of the positive allosteric modulator. Conclusions: Our work reveals that allosteric modulation of the D2L receptor can be affected by subtle ligand modifications. A change in configuration of a chiral carbon and/or minor structural modulator modifications are solely responsible for the functional outcome of the allosteric modulator.
PB Springer Nature
SN 1734-1140
YR 2022
FD 2022-01-22
LK https://hdl.handle.net/10347/39467
UL https://hdl.handle.net/10347/39467
LA eng
NO Żuk, J., Bartuzi, D., Silva, A.G. et al. Allosteric modulation of dopamine D2L receptor in complex with Gi1 and Gi2 proteins: the effect of subtle structural and stereochemical ligand modifications. Pharmacol. Rep 74, 406–424 (2022)
DS Minerva
RD 24 abr 2026