Screening of medicinal phytocompounds with structure-based approaches to target key hotspot residues in tyrosyl-DNA phosphodiesterase 1: augmenting sensitivity of cancer cells to topoisomerase I inhibitors

One of cancer's well-known hallmarks is DNA damage, yet it's intriguing that DNA damage has been explored as a therapeutic strategy against cancer. Tyrosyl-DNA phosphodiesterase 1, involved in DNA repair from topoisomerase I inhibitors, a chemotherapy class for cancer treatment. Inhibiting TDP1 can increase unresolved Top1 cleavage complexes in cancer cells, inducing DNA damage and cell death. TDP1's catalytic activity depends on His263 and His493 residues. Using molecular simulation, structure-based drug design, and free energy calculation, we identified potential drugs against TDP1. A multi-step screening of medicinal plant compound databases (North Africa, East Africa, Northeast Africa, and South Africa) identified the top four candidates. Docking scores for top hits 1-4 were -7.76, -7.37, -7.35, and -7.24 kcal/mol. Top hit 3 exhibited the highest potency, forming a strong bonding network with both His263 and His493 residues. All-atoms simulations showed consistent dynamics for top hits 1-4, indicating stability and potential for efficient interaction with interface residues. Minimal fluctuations in residue flexibility suggest these compounds can stabilize internal flexibility upon binding. The binding free energies of -35.11, -36.70, -31.38, and -23.85 kcal/mol were calculated for the top hit 1-4 complexes. Furthermore, the chosen compounds demonstrate outstanding ADMET characteristics, such as excellent water solubility, effective gastrointestinal absorption, and the absence of hepatotoxicity. Cytotoxicity analysis revealed top hit 2 higher probability of activity against 24 cancer cell lines. Our findings suggest that these compounds (top hits 1-4) hold promise for innovative drug therapies, suitable for both <i>in vivo</i> and <i>in vitro</i> experiments.