Structural insight into receptor-selectivity for lurasidone

Area of Science:

• Neuroscience
• Pharmacology
• Computational Chemistry

Background:

• Lurasidone is an antipsychotic with high affinity for dopamine D(2), serotonin 5-HT(2A), and 5-HT(7) receptors.
• It shows negligible affinity for histamine H(1) and muscarinic M(1) receptors, potentially reducing side effects like weight gain and sedation.

Purpose of the Study:

• Investigate the structural basis for lurasidone's high selectivity among aminergic G-protein coupled receptors (GPCRs).
• Understand the distinct binding profile of lurasidone compared to ziprasidone, which shares a similar chemical moiety.

Main Methods:

• Constructed homology models of lurasidone-GPCR complexes.
• Employed exhaustive docking and molecular dynamics simulations for refinement.
• Validated computational models with binding experiments of novel derivatives.

Main Results:

• Developed reliable structural models for D(2), 5-HT(2A), and 5-HT(7) receptors, revealing salt bridge interactions.
• Identified steric hindrance between lurasidone's norbornane/cyclohexane groups and H(1)/M(1) receptors, explaining lack of binding.
• Compared to olanzapine and ziprasidone, lurasidone's bulkier norbornane and cyclohexyl linker contribute to its selectivity.

Conclusions:

• Lurasidone's unique structural features confer high selectivity for target GPCRs, minimizing off-target interactions.
• This structure-based understanding aids in designing novel antipsychotics with improved binding profiles.
• Established computational protocols facilitate virtual screening and structure-based drug design for CNS therapeutics.