Molecular docking study and structure‐based design of novel camptothecin analogues used as topoisomerase I inhibitor

The paper describes the molecular docking study of the inhibition of human topoisomerase I (Top1), which is the molecular target of a diverse set of anticancer compounds such as glycinate, camptothecin, and its analogues. The reaction mechanisms involving their interaction with a transient Top1–DNA covalent complex inhibits the resealing of a single‐strand nick created by the enzyme to relieve superhelical tension in duplex DNA; this was confirmed using ICM‐Pro Molsoft program. Our research findings on this reaction indicate that its planner nature, the presence of some fragments on the lactone E‐ring, and the Pi–Pi interactions of the camptothecin drugs with DNA were directly responsible for its stable ternary complex with Top1. The molecular docking result of our study demonstrates that morpholinodoxorubicin (−32.835 kcal/mol), 9‐amino‐20‐RS‐camptothecin (−28.792 kcal), and camptothecin lysinate HCl (−28.224 kcal) best inhibit Top1 when compared with other National Service Center (NSC) compounds within our dataset. These compounds were further utilized in designing new potent antitumor compounds by attaching potent fragments to the lactone ring of the compounds. Most of these compounds were reported to be more active than the parent structure, some of which includes CLD‐12, CLD‐7, and CD‐9 with a binding affinity of −40.307, −36.743, and − 36.072 kcal/mol, respectively. Camptothecin is chemical compound responsible for inhibting the topoisomerase enzyme in cancer cells. The interaction between the Topoisomerase 1 and camptothecin analouges were studied using a molecular docking program. The information retrived from this interaction was then applied to the structure‐based design of more potent camptothecin.