Molecular Docking and Dynamics Simulation Revealed the Potential Inhibitory Activity of New Drugs against Human...

Area of Science:

• Biochemistry
• Molecular Biology
• Pharmacology

Background:

• Human Topoisomerase I (hTop1p) is crucial for DNA replication and a target for cancer chemotherapy.
• Camptothecin (CPT) is a known chemotherapeutic agent that inhibits hTop1p, leading to apoptosis in cancer cells.
• Artesunic acid derivatives, specifically compounds c6 and c7, have emerged as potential hTop1p inhibitors with possible antitumor effects.

Purpose of the Study:

• To computationally validate the experimental findings on compounds c6 and c7 as hTop1p inhibitors.
• To provide a detailed dynamic description of the interaction between these derivatives and the hTop1p-DNA complex.
• To elucidate the potential inhibitory mechanism of c6 and c7 against hTop1p.

Main Methods:

• Molecular docking analyses to assess ligand binding at the enzyme-DNA interface.
• Classical molecular dynamics simulations to evaluate the stability of the ligand-receptor complex over time.
• Calculation of noncovalent interactions to understand the binding mechanism.

Main Results:

• Compounds c6 and c7 demonstrated the ability to access the hTop1p-DNA interface.
• Molecular dynamics simulations confirmed stable binding poses for both derivatives.
• Analysis of noncovalent interactions provided insights into a potential CPT-like inhibitory mechanism.

Conclusions:

• Computational approaches support the experimental data for c6 and c7 as hTop1p inhibitors.
• These derivatives exhibit promising characteristics for further development as anticancer agents targeting hTop1p.
• The study provides a mechanistic basis for the observed inhibition by c6 and c7.