Evaluating the Reliability of Virtual Screening: Experimental Insights From Flavonoid Library Screen Targeting...

Area of Science:

• Biochemistry
• Pharmacology
• Computational Biology

Background:

• Computer-aided drug discovery (CADD) offers efficient screening of compounds but faces challenges with prediction reliability and false positives.
• Flavonoids are a class of compounds with potential therapeutic applications, but their efficacy requires rigorous validation.

Purpose of the Study:

• To evaluate the reliability of different docking tools for screening flavonoids against caspase-3.
• To identify potent flavonoid inhibitors of caspase-3.
• To assess the protective effects of identified flavonoids in a fatty liver disease model.

Main Methods:

• Screening of 354 flavonoids against caspase-3 using multiple docking tools.
• Comparison of computational predictions with in vitro enzymatic inhibition assays.
• Evaluation of selected flavonoids in cellular models of fatty liver disease.

Main Results:

• No single docking tool demonstrated high predictive accuracy, with consensus strategies showing limited improvement.
• Six lead flavonoid compounds were identified as caspase-3 inhibitors.
• Okanin, Irigenin, and Isoliquiritigenin demonstrated significant protection against liver cell death induced by amiodarone and oleic acid.

Conclusions:

• Individual docking programs have limitations in predicting flavonoid efficacy.
• An integrated computational approach is crucial for enhancing the reliability of virtual screening.
• This study provides a framework for designing effective flavonoid-based caspase inhibitors for liver diseases.