Dopamin 2 Reseptör Antagonisti Olarak Bazı Fitokimyasalların Antipsikotik Aktivitesinin Moleküler Doking Yöntemi ile Araştırılması

Abstract

Schizophrenia is a psychotic disorder characterized by delusions, hallucinations, disturbances of perception, thought, and behavior. Schizophrenia is caused by overactivation of the dopamine D2 receptor. Currently, dopamine D2 antagonists, which are classified as typical and atypical, and atypical partial agonists are used for the treatment of schizophrenia. However, the side effects of these drugs are quite high and they are insufficient to treat the negative and cognitive effects of schizophrenia. St. John's Wort, Peganum Harmala, Melissa Officinalis etc., which are known to be used in the treatment of schizophrenia in the literature. Although there are in vivo animal experiments of some Phytochemicals (Hypericin, Harmine, Rosmarinic Acid) contained in plants, there is no study that includes the binding energy and binding properties with the D2 receptor. Our aim is to investigate the effect of the phytochemicals contained in these plants as dopamine D2 receptor antagonists by using the AutoDock Vina program, one of the computer aided drug design methods, using the docking method, and to eliminate the extrapyrimidal side effects of the disease (restlessness, involuntary muscle spasm, etc.). In the first part of our study, a validation study was conducted for the 6CM4 PDB-encoded protein that forms the atypical antipsychotic drug Risperidone-linked Dopamine D2 Receptor (D2DR) complex, and the accuracy of the program and the chosen method was proven. In the validation study, the RMSD Value was found to be 1.967 Å. Since the RMSD value is less than 2 Å, the suitability of the AutoDock Vina program for the chosen method has been determined. In addition, the computational Ki value (1.87 nM) of the Risperidone ligand and the experimental Ki value (1.9 nM) were found to be quite close. In the second stage, the binding of 59 phytochemicals contained in 17 plants known to be used in traditional medicine in the treatment of schizophrenia in the literature, to the D2 receptor was examined for the first time using the AutoDock Vina program. As a result of this study, which was carried out for the first time, Hypericin was determined as the compound with the highest binding energy showing antagonist properties. However, according to the calculation results, the Hypericin compound could not cross the blood-brain barrier. The second best binding and the first compound to cross the blood brain barrier was determined as Demethoxyyangonin. In the third step, ADME (absorption, distribution, metabolism and excretion) properties were calculated using the swiss ADME program and some pharmacokinetic properties (blood-brain barrier crossing, gastrointestinal absorption) were investigated. In the fourth stage of the thesis, a similarity search was made for the Demethoxyyangonine compound in the ZINC15 database. Virtual ligand screening was performed for 99 compounds obtained with AutoDock Vina program. As a result of the calculations, it was found that the first 20 compounds could be promising candidates. The data obtained as a result of the research conducted in this thesis may contribute significantly to the design of new candidate antagonists that can be effective as D2 antagonists.