Design and in Silico Evaluation of Pseudoephedrine Derivatives with Reduced Blood-Brain Barrier Permeability
Keywords:
Computational Chemistry, Molecular Design, Pharmacokinetics, Molecular DockingAbstract
Pseudoephedrine is a widely used sympathomimetic agent for nasal decongestion. However, its central nervous system (CNS) side effects and potential misuse in the illicit synthesis of methamphetamine have raised concerns, prompting a search for peripheral-selective analog.
This study aimed to design novel pseudoephedrine derivatives that exhibit reduced blood-brain barrier (BBB) permeability while retaining biological activity, using in silico methods. In this study. Two pseudoephedrine derivatives were constructed by introducing tert-butyl (tBu) only, and both tert-butyl and phosphate at the meta position of the aromatic ring. Their physicochemical properties, pharmacokinetic profiles, and BBB permeability were predicted using SwissADME. Molecular docking was performed using the β2-adrenergic receptor (PDB ID: 2RH1) as the target to evaluate binding affinity. The derivative with both tBu and phosphate groups showed the most favorable profile, with a significantly reduced BBB permeability (as indicated by high Topological Polar Surface Area (TPSA)) and maintained comparable docking affinity to the original pseudoephedrine. TPSA, and synthetic accessibility scores supported its drug-likeness. These results demonstrate that rational functionalization of pseudoephedrine can improve pharmacokinetic selectivity by limiting CNS exposure. Although experimental validation was restricted due to regulatory limitations, this in silico study provides a promising scaffold for the development of safer sympathomimetic agents.
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