Virtual screening of naphthoquinone analogs for potent inhibitors against the cancer-signaling PI3K/AKT/mTOR pathway

Area of Science:

• Computational biology
• Medicinal chemistry
• Cancer signaling pathways

Background:

• The phosphoinositide 3-kinase/protein kinase B/mammalian target of rapamycin (PI3K/AKT/mTOR) pathway is frequently dysregulated in cancer, making its components attractive therapeutic targets.
• Naphthoquinone analogs, a class of plant metabolites and synthetic compounds, exhibit significant anticancer activity and are being explored for therapeutic potential.

Purpose of the Study:

• To computationally screen a diverse library of naphthoquinone analogs for their potential to inhibit key cancer-signaling proteins: PI3K, AKT, and mTOR.
• To identify and characterize a novel naphthoquinone analog with potent inhibitory activity against these three crucial cancer targets.

Main Methods:

• Employed structural computational biology approaches, including molecular docking, to evaluate the binding affinity of naphthoquinone analogs to PI3K, AKT, and mTOR.
• Conducted post-docking analyses such as binding energy calculations, dissociation constant estimations, and comparison with native ligands to validate docking accuracy.
• Performed ligand-based active site alignment to compare binding modes and similarities across the three target protein kinases.

Main Results:

• A novel naphthoquinone analog was identified as a top-ranked inhibitor across PI3K, AKT, and mTOR based on docking scores.
• Post-docking analyses confirmed favorable binding interactions, high binding energy, and low dissociation constants, supporting the compound's potential as a pan-PI3K/AKT/mTOR inhibitor.
• Comparative analysis revealed insights into the compound's binding characteristics within the active sites of the three kinases.

Conclusions:

• The study proposes a novel naphthoquinone analog as a promising anticancer agent targeting the PI3K/AKT/mTOR pathway.
• The findings provide a structural basis for understanding the compound's inhibitory mechanism against multiple cancer-related kinases.
• This research highlights the potential of computational methods in discovering new anticancer drug candidates from natural product-inspired scaffolds.