Interactions of 5- Iodotubercidin with binding site of serine/threonine - protein kinase Haspin; an ONIOM approach study

摘要

Each daughter cell has to receive the correct complement of chromosomes in mitosis. Some of mitotic kinases are critical to manage individualization of chromosomes. Haspin is newly discovered kinase with regulatory effect. Haspin protein has serine/ threonine kinase activity. Thr 3 of Histone H3 is the only substrate of Haspin to do phosphorylation. Highly potent and selective ligands are developed using organo non-metallic inhibitors. Non- metal centers prepare a big chemical chamber. Uncontrolled growth, survival and metastasis are some characteristics of cancer. These are caused because of perturbation of regulatory signaling pathways specially, kinases. Chemicals specifically inhibits such regulators, are targets for chemotherapy. Haspin (PDB ID: 3IQ7) is analyzed in present research. H-bond and Hydrophobic pocket interactions are studied with both docking and ONIOM methods. 5- Iodotubercidin-the mimetic structure of ATP- is one of effective inhibitors. To increase the efficacy and its attraction to binding site of the Haspin, it is suggested to modify the structure of drug to increase H-bond attraction. The main engaged amino acids in binding site that are responsible to produce H- bonds, are Glu~(606), Gly~(608), Asp~(611) and Gly~(653) .By modifying the drug it is possible to increase some sites, to engage more amino acids, close to present pocket. Gln~(614), Arg~(616) are closest functional amino acids based on primary structure. The same process will be done for hydrophobic pocket where Ile~(490), Gly~(491), Val~(498), Ala~(509), Phe ~(609), Leu~(656), and Ile~(686) are the main amino acids. Phe~(495), Phe~(499), Ile~(685), Val~(508) and Phe~(605) are suggested to be the next targets. Oxygen and Fluorine are found more effective than Iodine to make the system more stable. It is suggested to use the Oxygen or Fluorine as two electronegative elements instead of the Iodine.