Work

Machine Learning‐Driven Discovery of GABA‐A Ligands with Pronounced Neuroprotective Efficacy and Resistance to P‐gp Efflux

Year: 2025

Type: article

Abstract: Many studies have pointed to GABA‐A receptors as a promising therapeutic target for promoting recovery after stroke, owing to their neuroprotective efficacy and the enhancement of synaptic GABAergic currents. However, identifying nanomolar‐affinity ligands that evade P‐glycoprotein–mediated efflux can pose a significant challenge. To overcome this barrier, we developed a structure‐based machine learning workflow integrating molecular docking, which screened over 160 000 virtual analogs and identified eight synthetically accessible molecules. The synthesized compounds exhibited K i values at the GABA‐A receptor ranging from 50 to 1600 nM, with the most promising being 4d ( K i = 62 ± 11 nM) and 4h ( K i = 50 ± 3 nM), both of which confirmed PAM efficacy at GABA‐A receptors. Both ligands exhibited neuroprotective activity by attenuating glutamate‐induced Ca 2+ overload, preserving mitochondrial membrane potential and enhancing cell viability following oxygen–glucose deprivation in HT‐22 neurons. In MDR1‐MDCKII bidirectional assays, compound 4d (azetidine derivative) exhibited symmetric permeability (efflux ratio = 0.94), while 4h (bicyclic amino alcohol) was identified as a P‐gp substrate (efflux ratio = 2.04), suggesting that eliminating a single hydrogen‐bond donor at the amide tail is critical for minimizing efflux. Collectively, this study identifies compound 4d as a potent, low‐efflux GABA‐A receptor PAM with neuroprotective properties, supporting its further investigation.

Source: ChemMedChem

DOI: 10.1002/cmdc.202500605