Principal Component Analysis (PCA) of Molecular Descriptors for Improving Permeation through the Blood-Brain Barrier...

Despite its beneficial pharmacological effects in the brain, partly by modulating inositol phosphate multikinase (IPMK) activity, the therapeutic use of quercetin is limited due to its poor solubility, low oral bioavailability, and low permeability through the blood-brain barrier (BBB). We aimed to identify quercetin analogues with improved BBB permeability and preserved binding affinities towards IPMK and to identify the molecular characteristics required for them to permeate the BBB. Binding affinities of quercetin analogues towards IPMK were determined by molecular docking. Principal component analysis (PCA) was applied to identify the molecular descriptors contributing to efficient permeation through the BBB. Among 34 quercetin analogues, 19 compounds were found to form more stable complexes with IPMK, and the vast majority were found to be more lipophilic than quercetin. Using two distinct in silico techniques, insufficient BBB permeation was determined for all quercetin analogues. However, using the PCA method, the descriptors related to intrinsic solubility and lipophilicity (logP) were identified as mainly responsible for clustering four quercetin analogues (trihydroxyflavones) with the highest BBB permeability. The application of PCA revealed that quercetin analogues could be classified with respect to their structural characteristics, which may be utilized in further analogue syntheses and lead optimization of BBB-penetrating IPMK modulators as neuroprotective agents.