DNA topoisomerase-directed anticancerous alkaloids: ADMET-based screening, molecular docking, and dynamics simulation

Area of Science:

• Medicinal Chemistry
• Computational Biology
• Pharmacology

Background:

• Topoisomerases (Topo I and II) are vital targets in cancer therapy.
• Alkaloids represent a promising class of natural compounds for drug discovery.

Purpose of the Study:

• To identify novel anticancer agents from natural alkaloids.
• To evaluate the pharmacokinetic properties and inhibitory potential of alkaloids against Topoisomerase I and II.

Main Methods:

• In silico ADMET analysis and Lipinski's rule of five screening.
• Molecular docking simulations against Topoisomerase I and II active sites.
• Molecular dynamics simulations to assess complex stability.

Main Results:

• 18 out of 100 alkaloids met ADMET and Lipinski's rule criteria.
• Several alkaloids, notably oliveroline, demonstrated superior inhibition of Topo I and II compared to topotecan and etoposide.
• Molecular dynamics simulations confirmed the stable binding of oliveroline to Topo I and II.

Conclusions:

• Oliveroline and other identified alkaloids are potent inhibitors of Topoisomerase I and II.
• These alkaloids show significant potential as lead compounds for developing new anticancer drugs.
• Computational methods effectively identified promising natural product-based cancer therapeutics.