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Molecular docking study and structure‐based design of novel camptothecin analogues used as topoisomerase I inhibitor
Author(s) -
Arthur David Ebuka,
Uzairu Adamu
Publication year - 2018
Publication title -
journal of the chinese chemical society
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.329
H-Index - 45
eISSN - 2192-6549
pISSN - 0009-4536
DOI - 10.1002/jccs.201700314
Subject(s) - camptothecin , chemistry , topoisomerase , stereochemistry , docking (animal) , lactone , dna , ternary complex , molecular dynamics , enzyme , molecular model , combinatorial chemistry , biochemistry , computational chemistry , medicine , nursing
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.