Roskoski Robert
Blue Ridge Institute for Medical Research, 3754 Brevard Road, Suite 116, Box 19, Horse Shoe, NC 28742-8814, United States.
Pharmacol Res. 2016 Jan;103:26-48. doi: 10.1016/j.phrs.2015.10.021. Epub 2015 Oct 31.
Because dysregulation and mutations of protein kinases play causal roles in human disease, this family of enzymes has become one of the most important drug targets over the past two decades. The X-ray crystal structures of 21 of the 27 FDA-approved small molecule inhibitors bound to their target protein kinases are depicted in this paper. The structure of the enzyme-bound antagonist complex is used in the classification of these inhibitors. Type I inhibitors bind to the active protein kinase conformation (DFG-Asp in, αC-helix in). Type I½ inhibitors bind to a DFG-Asp in inactive conformation while Type II inhibitors bind to a DFG-Asp out inactive conformation. Type I, I½, and type II inhibitors occupy part of the adenine binding pocket and form hydrogen bonds with the hinge region connecting the small and large lobes of the enzyme. Type III inhibitors bind next to the ATP-binding pocket and type IV inhibitors do not bind to the ATP or peptide substrate binding sites. Type III and IV inhibitors are allosteric in nature. Type V inhibitors bind to two different regions of the protein kinase domain and are therefore bivalent inhibitors. The type I-V inhibitors are reversible. In contrast, type VI inhibitors bind covalently to their target enzyme. Type I, I½, and II inhibitors are divided into A and B subtypes. The type A inhibitors bind in the front cleft, the back cleft, and near the gatekeeper residue, all of which occur within the region separating the small and large lobes of the protein kinase. The type B inhibitors bind in the front cleft and gate area but do not extend into the back cleft. An analysis of the limited available data indicates that type A inhibitors have a long residence time (minutes to hours) while the type B inhibitors have a short residence time (seconds to minutes). The catalytic spine includes residues from the small and large lobes and interacts with the adenine ring of ATP. Nearly all of the approved protein kinase inhibitors occupy the adenine-binding pocket; thus it is not surprising that these inhibitors interact with nearby catalytic spine (CS) residues. Moreover, a significant number of approved drugs also interact with regulatory spine (RS) residues.
由于蛋白激酶的失调和突变在人类疾病中起因果作用，在过去二十年中，这类酶已成为最重要的药物靶点之一。本文描绘了27种FDA批准的与靶蛋白激酶结合的小分子抑制剂中的21种的X射线晶体结构。酶结合拮抗剂复合物的结构用于这些抑制剂的分类。I型抑制剂与活性蛋白激酶构象（DFG-天冬氨酸向内，αC-螺旋向内）结合。I½型抑制剂与DFG-天冬氨酸处于无活性构象时结合，而II型抑制剂与DFG-天冬氨酸向外的无活性构象结合。I型、I½型和II型抑制剂占据腺嘌呤结合口袋的一部分，并与连接酶的小和大亚基的铰链区形成氢键。III型抑制剂结合在ATP结合口袋旁边，IV型抑制剂不与ATP或肽底物结合位点结合。III型和IV型抑制剂本质上是变构的。V型抑制剂与蛋白激酶结构域的两个不同区域结合，因此是二价抑制剂。I-V型抑制剂是可逆的。相比之下，VI型抑制剂与其靶酶共价结合。I型、I½型和II型抑制剂分为A和B亚型。A型抑制剂结合在前裂隙、后裂隙和守门残基附近，所有这些都发生在蛋白激酶的小和大亚基之间的区域内。B型抑制剂结合在前裂隙和门区域，但不延伸到后裂隙。对有限可用数据的分析表明，A型抑制剂具有较长的驻留时间（数分钟至数小时），而B型抑制剂具有较短的驻留时间（数秒至数分钟）。催化脊柱包括来自小和大亚基的残基，并与ATP的腺嘌呤环相互作用。几乎所有批准的蛋白激酶抑制剂都占据腺嘌呤结合口袋；因此，这些抑制剂与附近的催化脊柱（CS）残基相互作用并不奇怪。此外，大量批准的药物也与调节脊柱（RS）残基相互作用。
