title: The inhibitory effect of helenalin on telomerase activity is attributed to the alkylation of the CYS445 residue: evidence from QM/MM simulations.
abstract: Enhanced telomerase activity is a hallmark in the majority of cancer cells. Thus, understanding the interactions between telomerase and its inhibitors is fundamentally important for the development of novel anticancer drugs without severe side effects. In this study, the covalent binding of helenalin to CYS445 of telomerase (PDB ID: 3DU6) was simulated using combined quantum chemical and molecular mechanical (QM/MM) methods. The results showed that the reaction was a reversible Michael-type addition and a hydrogen bond was formed between helenalin and the side chain of LYS416 of telomerase during the reaction procedure. The LYS416 residue is vital to telomere DNA recognition by interacting with DNA base through hydrogen bonds. The alkylation of CYS445 of telomerase by helenalin may interfere with the telomere DNA recognition at the telomerase active site, thus resulting in inhibition of the enzyme activity.
authors.affiliation: Department of Material and Chemical Engineering, Zhengzhou University of Light Industry, Zhengzhou 450002, Henan Province, PR China. Electronic address: zhangzq@zzuli.edu.cn.
authors.forename: Zhiqiang
authors.initials: Z
authors.lastname: Zhang
authors.affiliation: Department of Material and Chemical Engineering, Zhengzhou University of Light Industry, Zhengzhou 450002, Henan Province, PR China.
authors.forename: Liancai
authors.initials: L
authors.lastname: Xu
authors.affiliation: Department of Biology and Chemistry, City University of Hong Kong, Hong Kong Special Administrative Region. Electronic address: bhhonyun@cityu.edu.hk.
authors.forename: Hon-Yeung
authors.initials: HY
authors.lastname: Cheung
mesh_terms: D000478:Alkylation; D000818:Animals; D020134:Catalytic Domain; D003198:Computer Simulation; D003545:Cysteine / Q000737:chemistry; D004791:Enzyme Inhibitors / Q000737:chemistry*; D019476:Insect Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry; D007700:Kinetics; D008958:Models, Molecular; D011485:Protein Binding; D017433:Protein Structure, Secondary; D011789:Quantum Theory; D012717:Sesquiterpenes / Q000737:chemistry*; D045789:Sesquiterpenes, Guaiane; D019098:Telomerase / Q000037:antagonists & inhibitors* / Q000737:chemistry; D013816:Thermodynamics; D014231:Tribolium / Q000201:enzymology
chemical_list: D004791:Enzyme Inhibitors; D019476:Insect Proteins; D012717:Sesquiterpenes; D045789:Sesquiterpenes, Guaiane; C001329:helenalin; D019098:Telomerase; D003545:Cysteine
keywords: Anticancer; Helenalin; Pseudo-bond approach; Sesquiterpene lactone; Telomerase inhibitor