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■ 외부초청 세미나

일시 : 2008. 7. 9(목), 16:00
연사 : Dr. 김수경 (Caltech)
장소 : 신소재공학과 2427 강의실
제목 : Ensemble dockings and dynamic models of biogenic amine receptors


G protein-coupled receptors (GPCRs) form a large protein family that plays an important role in many physiological and pathophysiological processes with 50% of all recently launched drugs targeting GPCRs. In particular, the subfamily of biogenic amine binding GPCRs has provided excellent drug targets for the treatment of numerous diseases, such as schizophrenia, psychosis, depression, migraine, allergies, asthma, ulcers, and hypertension. However, there are major barriers to the clinical development of GPCR ligands; (1) A lack of subtype selectivity leads diverse drug side effects. (2) Lowered pharmacological efficacy of an agonist results in partial agonism or antagonism. Thus, the structural requirements for subtype selectivity and binding mechani! ! s m required for agonism or antagonism should be studied with the aid of molecular modeling. We are particularly interested in β2 adrenergic and serotonin (5-hydroxytrptamine, 5-HT) receptors which could be an ideal target to validate our current theoretical methods because of abundant information.
First, we validated our docking program (GenMSCDock) as well as first-principle GPCR structure prediction method (MembScream) using the x-ray structure of (S)-carazolol-bound β2 adrenergic receptor. Original experimental structure ranked as number one from 100 combinatorial set. The best complex of (S)-carazolol showed similar interactions with less than 0.5 Å root mean square deviations (RMSD) with the x-ray structure. Independent docking of (R)-carazolol revealed similar binding mode with decreased interaction which was consistent with its binding affinity.
To understand the subtype-selectivity of the 5-HT2B and 2C receptors, we studied the docking study of highly selective 5-HT2B antagonists from literature reports. The first 5HT2B/2C receptor indol urea antagonist (SB-206553, pA2, 5-HT2B: 8.5, pKi, 5-HT2C: 8.3) exhibited >100-fold selectivity over the 5-HT2A receptor. Conformational restriction within a six membered ring lowers the 5-HT2C affinity to the level observed for 5-HT2A without lowering the action on the 5-HT2B (pA2=7.27). More recently, highly selective 5-HT2B receptor antagonist, PRX-08066 (hHT2B Ki: 30nM) from EPIX pharmaceutical company, was under Phase II clinical trials for the treatment of pulmonary hypertension and hypoxia-induced pulmonary hypertension! ! syndromes caused by chronic obstructive pulmonary disease and mountain sickness. MembScream and GenMSCDock were used to predict the structure and the binding site. We present here the results of ensemble docking study into several lower-lying packing structures and molecular dynamic simulations in a realistic membrane environment. The results show the stability of the complex model and the sub-type selective key residues (V.53L, L3.29I, V4.60I, L6.58S). The simulations further revealed that the dissimilarity of water migration toward the NPxxYF motif (three times more waters in the agonist-bound structure) and the fluctuation of ligand (more flexible in agonist) affected the conformational change upon activation differently. The refined three-dimensional model would help the rational design of novel drugs for the 5-HT2B antagonists with higher subtype selectivity and lesser side effect.
 
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