3D-QSAR Studies Of Homocamptothecin Derivatives And Molecular Docking With Topoisomerase Ⅰ

In the current society, cancer has become a major issues that affect human health,Topoisomerase Ⅰ is a very important ribozyme, involved in DNA replication process. Due toits high expression in tumor cells than in normal cells Topoisomerase Ⅰ become a compellinganti-cancer drug target, Camptothecinis an alkaloid derived from the Chinese treeCamptotheca acuminata Decne. It acts on Topoisomerase and influence the DNAduplication. homocaptothecin is a new camptothecin derivative. It becomes a hotspot in recentresearch due to its high efficiency and low toxicity.Recently, computer aided drug design has become a more and more well-developedskill in drug development. In this research, we collected homocaptothecin derivatves frompublished reports and applied3D-QSAR analyses using the comparative molecular fieldanalysis(CoMFA) and comparative molecular similarity index analysis(CoMSIA) methods.Activity prediction models were established and the cross-validation correlation coefficientsfor CoMFA and CoMSIA were0.70and0.69, respectively, which showed the models arereliable.3D-QSAR results showed that the hydrophobic field of homocaptothecin derivativeshas a marked affect to the activity of the compounds. Structure-activity correlation studyprovides theoretical support for molecule modification, hence provides reference for thefurther synthesis modification of homocamptothecin compounds.The interaction pattern study of homocamptothecin compounds and Topoisomerase Ⅰ isbased on the crystal structure of Topoisomerase Ⅰ as well as the structures of the camptothecin.In this research, we use molecular docking technique to discover the interaction patternbetween the target and compounds. The compounds were able to dock into the active site ofthe Topoisomerase Ⅰ successfully. The homocaptothecin compounds with higher activity thantopotecan which is on the market were selected to perform molecular docking. The resultshowed that residues A:ASP533, A:THR718, B:DT10, A:ARG364, A:LYS436, C:DG12,A:ASN352, A:ASN722play a critical role in the molecular interaction and hydrogen bondformation. The introduced fluorine atom and hydroxyl group also take part in the hydrogenbond formation; aromatic ring introduced may help forming complex with Topoisomerase Ⅰ target through conjugated π-π interaction which makes the complex more stable.