Hydrogen bond dynamics and conformational flexibility in antipsychotics

Area of Science:

• Solid-state chemistry
• Computational chemistry
• Neuroscience

Background:

• Central nervous system disorders require effective treatments.
• Bioactive molecules with known tolerable moieties are key.
• Understanding solid-state characteristics and intramolecular dynamics of drugs is vital for pharmaceutical research and in silico drug discovery.

Purpose of the Study:

• To investigate the structural and molecular stability of three antipsychotic drugs: haloperidol, aripiprazole, and quetiapine hemifumarate.
• To compare experimental molecular vibrations with theoretical calculations for these antipsychotics.

Main Methods:

• Inelastic neutron spectroscopy (INS) was used to observe molecular vibrations.
• Periodic calculations using the Vienna ab initio simulation package (VASP) were performed for theoretical analysis.
• Comparison of experimental INS data with VASP calculations for crystalline antipsychotics.

Main Results:

• Most observed features in the lattice region were reasonably represented by theoretical calculations.
• The overall spectra were complex, preventing traditional assignment of all normal modes.
• Discrepancies between experimental and theoretical data highlight the complexity of antipsychotic molecular dynamics.

Conclusions:

• The study provides insights into the solid-state characteristics and molecular stability of key antipsychotics.
• Complex molecular dynamics in antipsychotics necessitate advanced analytical approaches.
• Drug candidate discovery should consider both receptor flexibility and active molecule dynamics for improved binding affinity predictions.