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Chem. J. Chinese Universities ›› 2009, Vol. 30 ›› Issue (12): 2409.

• Articles • Previous Articles     Next Articles

Characterization of Human Acrosin Active Site and Binding Modes with Its Inhibitors

ZHANG Jue, ZHENG Can-Hui, SHENG Chun-Quan, ZHOU You-Jun, ZHU Ju, LÜ Jia-Guo*   

  1. Department of Medicinal Chemistry, School of Pharmacy, Second Military Medical University, Shanghai 200433, China
  • Received:2009-03-18 Online:2009-12-10 Published:2009-12-10
  • Contact: Lü Jia-Guo. E-mail: ljg20060508@yahoo.com.cn
  • Supported by:

    上海市计生委科研基金(批准号: 2007JG02)和上海市重点学科建设项目(批准号: B906)资助.

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Abstract:

Acrosin is a promising target for contraceptive agents. Based on the previous homology modeling of human acrosin, the multiple copy simultaneous search(MCSS) methodology was used to explore the active site of human acrosin. The results show that all of three subsites(P1, P2 and G) are polar zones, and P1 is crucial for inhibitors′ binding. In addition, the edge of P1 and G as well as the bottom of P2 are hydrophobic, in which several important residues form hydrogen-binding interactions and electrostatic interactions. The key residues for ligand binding confirmed by MCSS calculations were consistent with the 3D structure of human acrosin complex and the experiments of site-directed mutagenesis on the animals. On the basis of above results, six of acrosin inhibitors, were docked into the active site of the human acrosin to elucidate their binding mode and the critical residues involved in binding. Our studies provide a basis for the rational design of novel acrosin inhibitors and the discovery of novel contraceptive drugs with high potency.

Key words: Acrosin; Multiple copy simultaneous search; Inhibitor; Contraceptive drug(KF950); Docking

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