Using novel click chemistry algorithm to design D3R inhibitors as blood-brain barrier permeants.
Alexander A KovalenkoYuri B PorozovEkaterina V SkorbSergey ShityakovPublished in: Future medicinal chemistry (2023)
Dopamine receptor D3 (D3R) has gained attention as a promising therapeutic target for neurological disorders. In this study, an innovative in silico click reaction strategy was employed to identify potential D3R binders. The ligand template, 1-phenyl-4-[4-(1H-1,2,3-triazol-5-yl)butyl]piperazine, with substitution at the 1,2,3-triazole ring, served as the starting point. Generated compounds underwent filtration based on their brain-to-blood concentration ratio (logBB), leading to the identification of 1-{4-[1-(decahydronaphthalen-1-yl)-1H-1,2,3-triazol-5-yl]butyl}-4-phenylpiperazine as the most promising candidate, displaying superior D3R affinity and blood-brain barrier (BBB) permeability compared to the reference ligand, eticlopride. Molecular dynamics simulations further supported these findings. This study presents a novel hit for designing D3R ligands and establishes a workflow utilizing in silico click chemistry to screen compounds with BBB permeability. The proposed click reaction-based algorithm holds significant potential as a valuable tool in the development of effective antipsychotic compounds.
Keyphrases
- blood brain barrier
- cerebral ischemia
- molecular dynamics simulations
- molecular docking
- machine learning
- deep learning
- endothelial cells
- metabolic syndrome
- risk assessment
- working memory
- high resolution
- uric acid
- neural network
- resting state
- subarachnoid hemorrhage
- brain injury
- electronic health record
- electron transfer
- binding protein
- capillary electrophoresis