Generalizable principles for tailoring deep eutectic solvents in alkaloid extraction: Insights from multi scale computational profiling of Piper nigrum and Zanthoxylum bungeanum.

Conventional extraction of bioactive alkaloids relies on volatile organic solvents. This study evaluated 21 deep eutectic solvents (DESs) through experimental screening and multi scale computational profiling to extract piperine (PIP) from Piper nigrum and hydroxy sanshools (HAS and HBS) from Zanthoxylum bungeanum. For rigid PIP, a choline chloride/1,2-butanediol (1:4, 20% water) DES achieved 60.11 mg/g (a 1.53-fold increase over methanol). For flexible sanshools, a urea/acetic acid (1:2, 30% water) DES yielded 59.36 mg/g (HAS) and 14.61 mg/g (HBS). Molecular dynamics revealed that extraction efficiency depends on topological and electrostatic complementarity. Specifically, ChCl/1,2-BD extracts PIP via synergistic hydrogen bonding and van der Waals interactions, whereas UR/HAc solubilizes sanshools through network reorganization, anchoring polar terminals while accommodating flexible chains. This work establishes three generalizable principles for rational DES design: electrostatic complementarity matching, spatial topology adaptation for rigid frameworks, and van der Waals compensation for flexible chains.