Exhaustive in silico design and screening of novel antipsychotic compounds with improved pharmacodynamics and blood-brain barrier permeation properties

Abstract

Antipsychotic drugs or neuroleptics are widely used in the treatment of psychosis as a manifestation of schizophrenia and bipolar disorder. However, their effectiveness largely depends on the blood-brain barrier (BBB) permeation (pharmacokinetics) and drug-receptor pharmacodynamics. Therefore, in this study, we developed and implemented the in silico pipeline to design novel compounds (n = 260) as leads using the standard drug scaffolds with improved PK/PD properties from the standard scaffolds. As a result, the best candidates (n = 3) were evaluated in molecular docking to interact with serotonin and dopamine receptors. Finally, haloperidol (HAL) derivative (1‐(4‐fluorophenyl)‐4‐(4‐hydroxy‐4‐{4‐[(2‐phenyl‐1,3‐thiazol‐4‐yl)methyl]phenyl}piperidin‐1‐yl)butan‐1‐one) was identified as a “magic shotgun” lead compound with better affinity to the 5-HT_2A, 5-HT_1D, D₂, D₃, and 5-HT_1B receptors than the control molecule. Additionally, this hit substance was predicted to possess similar BBB permeation properties and much lower toxicological profiles in comparison to HAL. Overall, the proposed rational drug design platform for novel antipsychotic drugs based on the BBB permeation and receptor binding might be an invaluable asset for a medicinal chemist or translational pharmacologist.

Communicated by Ramaswamy H. Sarma

Keywords:

• ADME-Tox
• antipsychotics
• blood-brain barrier permeation/penetration
• CNS-active medications
• dopamine and serotonin receptors
• molecular dynamics
• molecular docking
• P-gp affinity
• pharmacokinetics and pharmacodynamics

Author contributions

Conceptualization, R.T. and S.S.; methodology, R.T. and S.S.; software, R.T., Y.P; validation, R.T. and S.S.; formal analysis, R.T.; investigation, R.T.; resources, R.T.; data curation, S.S.; writing—original draft preparation, R.T.; writing—review and editing, R.T., S.S; visualization, R.T., S.S.; supervision, R.T., S.S.; project administration, R.T.; funding acquisition, S.S. “All authors have read and agreed to the published version of the manuscript.”

Data availability statement

MD simulation data are kept by S.S. and available from S.S.; R.T is responsible for keeping and giving access to the data for the rest of the in silico work.

Disclosure statement

No potential conflict of interest was reported by the author(s).

Institutional review board statement

“Not applicable”—in silico studies do not involve humans or animals and are compliant with the “Three Rs” in the European Union legislative framework.

Additional information

Funding

We thank the supporting organization providing grant 075-15-2021-1349 and the ITMO Fellowship.