First‐Principles Structure–Activity Relationship Insights Into Phenolic Scaffolds: QSAR Modeling and Drug‐Likeness Screening

مقال فى مجلة

2026

Phenolic compounds represent a structurally diverse class of bioactive
secondary metabolites renowned for their therapeutic potential, particularly
due to their antioxidant, anti-inflammatory, and anticancer properties. The
correlation between their molecular structure and biological efficacy, however,
remains an area of active investigation. This study presents an integrated
computational investigation of 49 phenolic derivatives combining density
functional theory (DFT)-based global reactivity descriptors determination,
quantitative structure–activity relationship (QSAR) modeling, and ADMET
(i.e., absorption, distribution, metabolism, excretion, and toxicity) profiling.
Using B3LYP/6-311++G** calculations, electronic descriptors are
systematically analyzed across a structurally diverse dataset. The results
reveal distinct substituent-dependent trends: electron-donating groups
enhance HOMO energies, decrease energy gaps, and increase softness,
favoring antioxidant and redox activity, whereas electron-withdrawing groups
increase hardness and electrophilicity, correlating with metabolic stability and
potential enzyme inhibition. Complementary QSAR models achieved high
predictive performance and identified LogP, electrophilicity, and hydration
energy as key toxicity predictors. ADMET analysis highlighted 4-ethoxyphenol,
2-fluorophenol, and 4-cyanophenol as promising drug-like scaffolds with high
gastrointestinal absorption, favorable blood–brain barrier permeability, and
minimal predicted toxicity. Overall, this study provides structure–activity
insights for phenolic scaffolds by bridging electronic structure with
pharmacokinetic behavior and prioritizing candidates for future drug design
and experimental validation.

• نوع عمل المنشور: ورقة علمية