Exploring the Interactions between two Ligands, UCB-J and UCB-F, and Synaptic Vesicle Glycoprotein 2 Isoforms

Area of Science:

• Computational chemistry and molecular modeling
• Neuroscience and neuropharmacology
• Structural biology

Background:

• Synaptic vesicle glycoprotein 2 (SV2) plays a crucial role in regulating synaptic function.
• Understanding ligand interactions with SV2 isoforms is key to developing targeted therapeutics.
• Existing knowledge on the specific binding mechanisms of UCB-J and UCB-F to SV2 isoforms is limited.

Purpose of the Study:

• To investigate the binding efficiency and selectivity of UCB-J and UCB-F ligands to different SV2 isoforms using in silico methods.
• To elucidate the molecular interactions governing the selectivity of UCB-J and UCB-F for SV2 isoforms.
• To provide atomic-level insights for the design of novel SV2-targeting tracers.

Main Methods:

• In silico modeling, including molecular docking and large-scale molecular dynamics simulations.
• Analysis of binding patterns, interaction types (hydrogen bonding, hydrophobic, π-π, cation-π), and binding free energies.
• Detailed examination of ligand-protein residue interactions within SV2 binding pockets.

Main Results:

• UCB-J exhibits high selectivity for SV2A, attributed to a unique combination of hydrogen bonding and cation-π interactions involving its pyridine moiety.
• UCB-F demonstrates selectivity across three SV2 isoforms, driven by π-π interactions and hydrogen bonding.
• Detailed molecular interaction fingerprints were identified for both ligands across different SV2 isoforms.

Conclusions:

• The study provides a detailed molecular understanding of UCB-J and UCB-F binding to SV2 isoforms.
• Specific interaction patterns explain the observed selectivity of UCB-J and UCB-F.
• These findings support the future development of selective SV2-targeting tracers for neurological diseases.