G-protein kenetli reseptörlerin aktivasyon mekanizmalarının çok boyutlu modelleme yöntemleri ile incelenmesi

G-Protein Coupled Receptors (GPCRs) constitute the largest class of membrane proteins involved in signal transduction across the biological membranes. They are essential targets for cell signaling and are of great commercial interest to the pharmaceutical industry. They make up ~50% of clinically marketed drugs and ~25% of top-selling drugs targeting this receptor family. Recent advances made in molecular biology and computational chemistry open new avenues in designing novel therapeutic compounds. Molecular biology has provided the crystal structures of several GPCRs in active and inactive states, which can be used as accurate templates in modeling studies. Computational chemistry offers a range of simulation, multi-scale modeling and virtual screening tools for definition and analysis of protein-ligand, protein-protein interactions. Development of new techniques on statistical methods and free energy simulations helps to predict novel optimal ligands. In this thesis, our aim is to use all these advances by developing an integrated approach for better understanding of activation mechanisms of GPCRs, which will help to rationalize the ligand screening process and facilitate design of new therapeutic compounds for these targets. Defining the activation mechanisms and atomistic determinants of ligand binding to GPCR targets would allow greater safety in human life. The thesis includes four chapters in which various binding interaction mechanisms based on solved and unsolved GPCR crystal structures are studied in detail. Specifically, activation mechanisms of Dopamine D2, Chemokine receptor type 5 and κ-opioid type GPCRs are elucidated using different in-silico approaches as explained below: