Best poses

Chronic exposure to ultraviolet (UV) radiation is known to induce the formation of both cyclobutane pyrimidine dimers (CPDs) and Dewar valence photo-adducts (DVs) in DNA. While CPDs occur at a frequency three or four times greater than DVs, recent studies have unveiled that the latter display superior selectivity and significant stability in interaction with the human DNA/Topoisomerase 1 complex, highlighting notable anti-melanoma properties. To better comprehend the behaviour of these thymine-based photoadduct ligands (DV) in a biological context, we conducted four all-atom molecular dynamic simulations spanning 1 microsecond. These simulations examined the stability and conformational changes of two DNA/TOP1-DV complexes in solution, and their molecular counterparts, DNA/TOP1-biomimetic thymine dimers. Results from root-mean-square deviation (RMSD) and root-mean-square fluctuation (RMSF) analyses unequivocally confirmed increased stability of the DNA/TOP1-DV complexes throughout the simulation duration. Furthermore, we performed detailed interaction analyses, uncovering the presence of salt bridges, hydrogen bonds, water-mediated interactions, hydrophobic interactions, and π stacking interactions. Ultimately, pinpointing the non-covalent interactions within the complexes enabled the evaluation of receptor residues involved in these interactions and proposed a potential TOP1 inhibition mechanism. These findings emphasise the prospective use of DV photo-adducts as antitumor agents. Our study may pave new avenues in cancer therapy.