Biphenyl scaffold for the design of NMDA-receptor negative modulators: molecular modeling, synthesis, and biological activity.
Dmitry S KarlovNadezhda S TemnyakovaDmitry A VasilenkoOleg I BaryginMikhail Y DronArseniy S ZhigulinElena B AverinaYuri K GrishinVladimir V GrigorievAlexey V Gabrel'yanViktor A AniolNatalia V GulyaevaSergey V OsipenkoYury I KostyukevichVladimir A PalyulinPetr A PopovMaxim V FedorovPublished in: RSC medicinal chemistry (2022)
NMDA ( N -methyl-d-aspartate) receptor antagonists are promising tools for the treatment of a wide variety of central nervous system impairments including major depressive disorder. We present here the activity optimization process of a biphenyl-based NMDA negative allosteric modulator (NAM) guided by free energy calculations, which led to a 100 times activity improvement (IC 50 = 50 nM) compared to a hit compound identified in virtual screening. Preliminary calculation results suggest a low affinity for the human ether-a-go-go-related gene ion channel (hERG), a high affinity for which was earlier one of the main obstacles for the development of first-generation NMDA-receptor negative allosteric modulators. The docking study and the molecular dynamics calculations suggest a completely different binding mode (ifenprodil-like) compared to another biaryl-based NMDA NAM EVT-101.
Keyphrases
- molecular dynamics
- major depressive disorder
- small molecule
- density functional theory
- bipolar disorder
- endothelial cells
- molecular dynamics simulations
- protein protein
- photodynamic therapy
- copy number
- dna methylation
- induced pluripotent stem cells
- mass spectrometry
- cerebrospinal fluid
- smoking cessation
- transcription factor
- genome wide identification
- light emitting