Department of Biochemistry, Faculty of Science, Kasetsart University, 50 Phaholyothin Rd, Chatuchak, Bangkok, 10900, Thailand.
J Mol Model. 2013 Feb;19(2):497-509. doi: 10.1007/s00894-012-1559-0. Epub 2012 Sep 7.
The structural diversity observed across protein kinases, resulting in subtly different active site cavities, is highly desirable in the pursuit of selective inhibitors, yet it can also be a hindrance from a structure-based design perspective. An important challenge in structure-based design is to better understand the dynamic nature of protein kinases and the underlying reasons for specific conformational preferences in the presence of different inhibitors. To investigate this issue, we performed molecular dynamics simulation on both the active and inactive wild type epidermal growth factor receptor (EGFR) protein with both type-I and type-II inhibitors. Our goal is to better understand the origin of the two distinct EGFR protein conformations, their dynamic differences, and their relative preference for Type-I inhibitors such as gefitinib and Type-II inhibitors such as lapatinib. We discuss the implications of protein dynamics from a structure-based design perspective.
在追求选择性抑制剂时，观察到蛋白激酶之间的结构多样性，导致略微不同的活性位点腔，这是非常理想的，但从基于结构的设计角度来看，这也可能是一个障碍。基于结构的设计中的一个重要挑战是更好地理解蛋白激酶的动态性质以及在存在不同抑制剂时特定构象偏好的基础原因。为了研究这个问题，我们对具有 I 型和 II 型抑制剂的活性和非活性野生型表皮生长因子受体 (EGFR) 蛋白进行了分子动力学模拟。我们的目标是更好地理解两种不同 EGFR 蛋白构象的起源、它们的动态差异以及它们对吉非替尼等 I 型抑制剂和拉帕替尼等 II 型抑制剂的相对偏好。我们从基于结构的设计角度讨论了蛋白质动力学的意义。
