报告题目：优化药效物治疗指数（Optimizing Pharmacophore Therapeutic Indices ）
报告人：Mahesh Narayan（美国德克萨斯大学化学系教授）
报告地点：校本部E楼2楼纳米所会议室
报告时间：2014.10.18，10:30
主办：环化学院
报告简介：
Halogen bonding interactions between halogenated ligands and proteins were examined using the crystal structures deposited to date in the PDB. The data was analyzed as a function of halogen bonding to main chain Lewis bases, viz. oxygen of backbone carbonyl and backbone amide nitrogen. This analysis also examined halogen bonding to side-chain Lewis bases (O, N, and S) and to the electron-rich aromatic amino acids. The data reveals that while fluorine and chlorine have strong tendencies favoring interactions with the backbone Lewis bases at glycine, the trend is not restricted to the achiral amino acid backbone for larger halogens. Halogen side-chain interactions are not restricted to amino acids containing O, N, and S as Lewis bases. Electron-rich aromatic amino acids host a high frequency of halogen bonds as does Leu. A closer examination of the latter hydrophobic side chain reveals that the "propensity of interactions" of halogen ligands at this oily residue is an outcome of strong classical halogen bonds with Lewis bases in the vicinity. Furthermore, an examination of Θ1 (C-X···O and C-X···N) and Θ2 (X···O-Z and X···N-Z) angles reveals that very few ligands adopt classical halogen bonding angles, suggesting that steric and other factors may influence these angles.
Outcomes from understanding halogen bonding trends in the PDB were applied towards rational drug design. Currently there are no specific pharmacological therapies (drugs) to treat post traumatic stress disorder (PTSD). Emerging data reveal that the opioid receptor-like 1 gene (Oprl1), encoding the nociception (NOP)/orphanin FQ receptor, is involved in stress-mediated enhancement of amygdala-dependent fear in PTSD syndrome. Here, we attempted to design and develop specific novel nociception receptor agonists with the objective of achieving better receptor specificity. A structure based drug design method was used while availing of the crystal structure of nocicpetin receptor in the PDB. Halogen bonding was fully explored in designing the drugs. The results presented through our study illustrate the application of halogen bonding in rational drug design.