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报告题目：How molecular dynamics simulations may be applicable to the structure-based design of kinase drugs

报告人：Yibing Shan (单一兵), Ph.D.

              Sr. Research Scientist: D. E. Shaw Research

             北京计算科学研究中心讲座教授

             Member of the Board of Reviewing Editors of eLife

时    间：2017年6月29日（星期四）15:00

地    点：医学部生化楼三层中厅

主持人：云彩红教授

摘    要：Protein kinases are one of the most important families of drug targets for the pharmaceutical industry, and, although the number of FDA-approved kinase drugs continues to increase, finding drug molecules that effectively and selectively target these systems remains a great challenge. A critical component, one that is not unique to kinases, yet so far has not been systematically exploited, is the role of conformational dynamics in the process of drug binding. Anton, a specialized supercomputer for performing molecular dynamics simulations, has enabled simulations on the micro- to millisecond timescale, which are long enough to capture the details of protein conformational rearrangements and drug binding.  Anton simulations have been used not only to visualize the complete binding process of kinase drugs such as lapatinib, gefitinib, and dasatinib, but also to follow critical protein kinase conformational changes such as the DFG flip and the rearrangement of the activation loop. Conformational dynamics can also help to elucidate functional differences, as in the case of EGFR, where cancer mutants appear to “over-stabilize” EGFR kinase relative to wild type, thereby promoting dimerization that leads to aberrant activation. Another promising direction is the use of long-timescale simulations to discover cryptic binding sites, features that may be absent from crystal structures but useful in the development of selective kinase inhibitors.

报告人代表性论文：

(1) Needham SR, Roberts SK et al. (2016). EGFR oligomerization organizes kinase-active dimers into competent signalling platforms. Nature Communications, 7, 13307. [Correspondent Author]

(2) Foda ZH, Shan YB et al. (2015). A dynamically coupled allosteric network underlies binding cooperativity in Src kinase.  Nature Communication. 6, 5939 [Correspondent Author]

(3) Shan YB, Gnanasambandan K et al. (2014). Molecular basis for pseudokinase-dependent autoinhibition of JAK2 tyrosine kinase. Nature Structural & Molecular Biology. 21, 579-584 [Correspondent Author]

(4) Arkhipov A, Shan YB et al. (2013). Her2 activation mechanism reflects evolutionary preservation of asymmetric ectodomain dimers in the human EGFR family. eLIFE 2:e00708 [Correspondent Author]

(5) Arkhipov A., Shan YB et al. (2013). Architecture and membrane interactions of the EGF receptor. Cell 152 (3) 557-569  [Correspondent Author] [Faculty 1000. Recommendation]

(6) Shan YB, Arkhipov A et al. (2013). Transitions to catalytically inactive conformations in EGFR kinase. Proceedings of the National Academy of Sciences 110:7270-7275 [Correspondent Author]

(7) Shan YB, Eastwood MP et al. (2012). Oncogenic Mutations Counteract Intrinsic Disorder in the EGFR Kinase and Promote Receptor Dimerization. Cell 149 (4) 860-870 [Correspondent Author] [Faculty 1000 Recommendation]