Sean Swale/Human Thrombin Inhibitor
From Proteopedia
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<Structure load='3utu' size='500' frame='false' align='right' |caption='Human Thrombin' scene='Insert optional scene name here' StructureSection> | <Structure load='3utu' size='500' frame='false' align='right' |caption='Human Thrombin' scene='Insert optional scene name here' StructureSection> | ||
<scene name='Sean_Swale/Human_Thrombin_Inhibitor/Active_site/1'>Total active site</scene> | <scene name='Sean_Swale/Human_Thrombin_Inhibitor/Active_site/1'>Total active site</scene> | ||
| + | ===Reasons to develop another Thrombin Inhibitor=== | ||
| + | Thrombin is a (structure) with four binding sites. | ||
| + | In order to prevent venous thrombosis (blood clots) after surgery or during dialysis when blood is in contact with artificial devices, Heparin is normally administered. Unfortunately Heparin is neutralized by plasma proteins in the blood, is less efficient for the inhibition of clot bound thrombin, and can trigger an enormous immune response. Antithrombotic drugs like Hirudin will be given if Heparin is not able to be tolerated or if the person receives regular dialysis. (Insert reasons why hirudin sucks) Chemists have been working on designer drugs to increase selectivity and potency. | ||
| + | ===Phe-Pro-p-amidinobenzylamine=== | ||
| + | An early experiment to find a better thrombin inhibitor yielded a structure that was able to bond to the P1 and P2 sites of Thrombin effectively. In 1996 Lilly research laboratories created D-Phe-Pro-p-amidinobenzylamine by making improvements on the previous structure D-Phe-Pro-Agmatine. The new compound they created bonded to thrombin 130x more than it did to trypsin (also a serine protease), and it was highly selective of thrombin over fibrinolytic enzymes such as 26,000x greater with plasmin, 170,000x greater than t-Pa, and 400,000x greater than urokinase. Its selectivity was gained by binding its nitrogens on the benzamidine group by hydrogen bonding to Asp 189, and by fitting its benzamidine benzene into a hydrophobic pocket with Ser 214-Glu 217 and Asp 189-Glu 192 on the other side. The proline residue is in another hydrophobic pocket made up of His 57, Tyr 60A, Leu 99, and Trp 60D. The rest of this structure is unimportant on review of inhibitor 65 because only the amidinobenzylamine which occupies R1 and the proline which occupies the R2 sit are the same residues on inhibitor 65. | ||
| + | ===P3 and P4 of Inhibitor 65=== | ||
| + | Inhibitor 65 additionally has a P4 sulfonyl group with a methoxy group at the end of the residue. It sits in tight VanderWaals structure with the surrounding residues Leu 99, Tyr 60A, Arg 97, Glu 97, and Asn 98.Additionally, the chlorine points to the carbonyl oxygen of Asn 98 and there is a weak Cl-π bond with Trp 215. For the P3 residue, there the backbone of asparagine forms and anti parallel beta sheet with Gly 216. The alkylated asparagine’s NH binds to water which then connects to Glu 192, and the NH of Gly 219 and Gly 216. | ||
This is the <scene name='Sean_Swale/Human_Thrombin_Inhibitor/Thrombin_active_site/2'>active site</scene> of thrombin | This is the <scene name='Sean_Swale/Human_Thrombin_Inhibitor/Thrombin_active_site/2'>active site</scene> of thrombin | ||
Revision as of 17:57, 15 November 2012
Human Thrombin Inhibitor
Thrombin is a serine protease that cleaves fibrinogen to allow fibrin to form stringy networks that trap red blood cells to form clots. Thrombin is a serine protease because it cleaves fibrinogen with its serine residue. Thrombin when made by the body is tethered to blood vessels so that it cannot cause clots throughout the body causing strokes and heart attacks. Additionally, thrombin is only activated for a few seconds to limit the clotted area to the injured area[1]. In cases such as dialysis a blood thinner like hirudin is needed to make sure a blood clot is not created in the body. Unfortunately, when hirudin was used it could be required up to four times per week which heavily taxes the body. Thus new thrombin inhibitors with greater specificity for the thrombin binding site were developed in vitro such as inhibitor 65. [2]
Introduction
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