Allosteric modulation of dopamine D(2L) receptor in complex with G(i1) and G(i2) proteins: the effect of subtle structural and stereochemical ligand modifications

BACKGROUND: Allosteric modulation of G protein-coupled receptors (GPCRs) is nowadays one of the hot topics in drug discovery. In particular, allosteric modulators of D(2) 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 D(2) 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 D(2L) 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 D(2L) 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. GRAPHICAL ABSTRACT: [Image: see text] SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s43440-021-00352-x.