La thrombose est le plus important processus pathologique sous-jacent à de nombreuses maladies cardiovasculaires, qui sont responsables d’une mortalité élevée dans le monde entier. Dans cette thèse, la conception assistée par ordinateur de nouveaux agents antithrombotiques capables d’inhiber deux types de récepteurs situés à la surface des plaquettes a été appliquée. Le premier - αIIbβ3 - est responsable de l’interaction des plaquettes activées avec le fibrinogène pour former des caillots, tandis que le second – le thromboxane A2 – est responsable de l’activation des plaquettes par l’un des agonistes excrétés par les plaquettes activées. Afin d’atteindre cet objectif, différents types de modèles ont été développés en utilisant les informations expérimentales disponibles et la structure des complexes protéine-ligand, comprenant des modèles QSAR, des pharmacophores 3D basés sur la structure de la protéine ou du ligand, des pharmacophores 2D, des modèles basés sur la forme et sur le champ moléculaire. L’ensemble des modèles développés ont été utilisés en criblage virtuel. Cette étude a abouti sur la suggestion de nouveaux antagonistes potentiels des récepteurs αIIbβ3 et thromboxane A2. Les antagonistes de αIIbβ3 suggérés pouvant se lier soit à la forme ouverte soit à la forme fermée du récepteur ont été synthétisés et testés expérimentalement. L’expérience montre qu’ils font preuve d’une forte activité; de plus, certains des composés conçus théoriquement sont plus efficaces que le Tirofiban, qui est un médicament commercialisé. Les antagonistes recommandés du récepteur thromboxane A2 ont déjà été synthétisés mais les tests biologiques n’ont pas encore été complétés. / Thrombosis is the most important pathological process underlying many cardiovascular diseases, which are responsible for high mortality worldwide. In this theses the computer-aided design of new anti-thrombotic agents able to inhibit two types of receptors located on the surface of the platelets has been applied. The first one - αIIbβ3 - is responsible for the interaction of activated platelets with fibrinogen to form clots, whereas the second one - thromboxane A2 - is responsible for platelet activation by one of agonists excreted by activated platelets. To achieve this, different types of models have been developed using experimentally available information and structure of protein-ligand complexes. This concerns: QSAR models, structure-based and ligand-based 3D pharmacophore models, 2D pharmacophore models, shape-based and molecular field-based models. The ensemble of the developed models were used in virtual screening. This study resulted in suggestion of new potential antagonists of αIIbβ3 and thromboxane A2 receptors. Suggested antagonists of αIIbβ3 able to bind either open or closed form of the receptor have been synthesized and tested experimentally. Experiments show that they display high activity; moreover some of theoretically designed compounds are more efficient than Tirofiban – the commercialized drug molecule. The recommended antagonists of thromboxane A2 receptor have been already synthesized but biological tests have not been completed yet.

Thrombosis is the most important pathological process underlying many cardiovascular diseases, which are responsible for high mortality worldwide. In this theses the computer-aided design of new anti-thrombotic agents able to inhibit two types of receptors located on the surface of the platelets has been applied. The first one - αIIbβ3 - is responsible for the interaction of activated platelets with fibrinogen to form clots, whereas the second one - thromboxane A2 - is responsible for platelet activation by one of agonists excreted by activated platelets. To achieve this, different types of models have been developed using experimentally available information and structure of protein-ligand complexes. This concerns: QSAR models, structure-based and ligand-based 3D pharmacophore models, 2D pharmacophore models, shape-based and molecular field-based models. The ensemble of the developed models were used in virtual screening. This study resulted in suggestion of new potential antagonists of αIIbβ3 and thromboxane A2 receptors. Suggested antagonists of αIIbβ3 able to bind either open or closed form of the receptor have been synthesized and tested experimentally. Experiments show that they display high activity; moreover some of theoretically designed compounds are more efficient than Tirofiban - the commercialized drug molecule. The recommended antagonists of thromboxane A2 receptor have been already synthesized but biological tests have not been completed yet.