Molecular Modeling And Drug Design Targeting CB1 Cannabinoid Receptor And Estrogen Receptors

Computer aided drug design (CADD) has become an indispensable tool in the field of drug discovery in modern society. In this thesis, relevant techniques of CADD were employed to investigate CB1 cannabinoid receptor (CB1R) and estrogen receptor (ERs).In Chapter 1, some fundamentals and common strategies of CADD were introduced and the outline of the thesis was also demonstrated.In Chapter 2, ligand- and structure- based drug design methods were utilized to investigate the interactions between CB1R and its antagonists. Firstly, a pharmacophore model was constructed based on 31 CB1 antagonists. This model was then validated by test set prediction and simulated virtual screening evaluation. In the meantime, a homology model of CB1R was created based on the crystal structure of humanβ2-adrenergic receptor (β2-AR). The minimized and optimized model was then subjected to an induced fit docking process in order to identify the binding modes of CBIR with relevant antagonists. The information obtained from these two types of models should be useful for the discovery of novel CB1R antagonists.In Chapter 3, some techniques and strategies of CADD were used to develop novel ligands of estrogen receptors. Firstly, a core-structure database was constructed, and then 10 novel ligands were designed with a core-hopping strategy. At the same time, a combined strategy of virtual screening was utilized to screen two commercial databases, namely Maybridge and Enamine.20 active compounds were identified with the yeast-two-hybrid (Y2H) assays, among which several showed quite high selectivity. Some high-potency molecules were then subjected to transient transfection and MTT assays in order to test the activities of them on cell levels. The highly selective ligands discovered could serve as molecular probes to investigate the functionalities of ERa and ERβ. They could also be used as lead compounds to develop novel selective estrogen receptor modulators (SERMs).In Chapter 4, a brief summary was given about all the content of the thesis.