The Design And Synthesis Of Thrombin Inhibitor

Thrombin-embolism is a serious disease that disserves the elderly's health at present. The number of patients is increasing quickly; more and more researchers pay attention to how to prevent and cure thrombus, and do their best to find out effective medications. Thrombin plays an importent role in the processes of thrombosis. So thrombin becomes a new target for researchers to study, and thrombin inhibitors also become imporant anti-thrombosis drugs. Different kinds of thrombin inhibitors are on sale, especially, benzoxazinone derivatives are new compounds of anti-thrombosis, more and more researchers pay attention to them because they have simple structures and can be synthesed easily.At present, the reported thrombin inhibitors were gained from a random selection. The leading compounds and their derivatives have been designed in detail by the foreign research teams. There are different kinds of thrombin inhibitors, in which bezoxazinone derivatives show satisfactory results in inhibiting serine protease on the intensity and selectivity. However, in the further structural optimization and transformation, due to the lack of mechanisms with thrombin, these inhibitors showed out many limitations. New leading compounds by computer-aided drug design are hoped to be discovered.At first, the reported benzoxazinone derivatives were studied by molecular docking software AUTODOCK4.0 to study the joint configuration between the inhibitors and the enzyme. The active set of the target cavity with the combination of the key residues were also identified. And the linear relationship between the inhibition constant of inhibitor with inhibitory activity were also dicussed.Docking results showed that inhibitors occupy the active site of thrombin and showed hydrophobic interaction with the hydrophobic cavity of the thrombin. The side chain of the particular residue of the target enzyme site can form a hydrogen bond with the ligand molecular, which can enhance the binding force. Through analysis of the docking results, the common feature of these inhibitors as follows: hydrophobic planar structure of the mother ring, which could form two conservative hydrogen bonds to the donor and the receptor; which could also point to the hydrophobic cavity as well as the formation of additional hydrogen bonds to the receptor.Then, on the basis of the molecular docking, molecular designed software SYBYL was used to analyze three-dimensional quantitative structure-activity relationship of benzoxazinone derivatives. Comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) methods were used to study these derivatives. The model had a good predictive capability, from which the useful three-dimensional big group, hydrophobic structure, electric and hydrogen-bonding groups as well as receptor's distribution on the binding-site were determined.On the basis of the work mentioned above, a series of new class of benzoxazine derivatives were designed, and their predicted activities were higher than the old ones. The synthesisi routes of new compounds were designed, and several compounds have been synthesed.