Trombin Inhibitörlerinin Moleküler Modelleme Çalışmaları Mmm

Abstract

Coagulation is the transformation of fibronogen to fibrin which is the basis of clot at blood circulation. Up till now 13 factors playing a role in clot formation have been discovered. In normal operation of all of these factors, the thromboplastine that is located in injured tissue translates the prothrombin which is in circulation to thrombin. This also influences the fibrinogen and leads the fibrinogen to turn into fibrin. The enzyme that catalyzes the conversion of fibrinogen to fibrin is Thrombin. Thrombin which leads to blood coagulation is a serine protease enzyme and so is produced in the amounts of the body needs. The drugs that inhibit the formation and development of clots on lining of blood vessels are called anticoagulants. Also, intravascular clot formation creates a significant risk factor in human life. Due to the task of thrombin at the last stage of blood clotting it continues to be the main target in the development of new anticoagulant drugs. Today, the anticoagulant drugs used as direct thrombin inhibitor (DTI) are hirudin, lepirudin, bivaluridin, and monovalent: argatroban, dabigatran. The single oral drug dabigatran is immediately broken down by the effect of the moisture in the air. The disadvantages of other inhibitors are that they can’t be taken by orally and due to a genetic disorder they shouldn’t be used by the patients who are lack of anti-thrombin III. For this reason, most of today’s pharmaceutical companies are working on the design of new drugs that is argatroban-based and so can be taken orally. The aim of this study is to investigate a direct thrombin inhibitor that has a small molecular structure and weight and can be taken orally on the basis of Argatroban and its basic structures. Firstly appropriate docking program and thrombin structure should be determined that is suitable for our thrombin system. To determine this, validation study was carried out with AutoDock and AutoDock Vina Programs by using 1k22, 1dwc and 1dwd coded structures that consist of the coordinates of three-dimensional structure of thrombin. According to the results of single docking 4 validation study, 1dwc structure which has the smallest RMSD value and the lowest binding energy and AutoDock Vina Program which gives these results are found to be appropriate. In the light of the single docking studies, the parts that are commonly seen in TAME structure and Argatroban which is 1dwc structure are drawn by ZINC data bank. A data set was prepared that consists of 578 structures. Due to the calculation results of virtual ligand screening (VLS) that is obtained by using the data set and AutoDock Vina program, it is observed that the RMSD value of 175 molecules is smaller than 2 Ǻ. 20 of these structures have the lowest binding energy and they will shed light to us in the design of new inhibitors on the future studies.