Department of Biomedical Engineering, Boston University, Boston, MA 02215, USA.
Proc Natl Acad Sci U S A. 2011 Aug 16;108(33):13528-33. doi: 10.1073/pnas.1101835108. Epub 2011 Aug 1.
Despite the growing number of examples of small-molecule inhibitors that disrupt protein-protein interactions (PPIs), the origin of druggability of such targets is poorly understood. To identify druggable sites in protein-protein interfaces we combine computational solvent mapping, which explores the protein surface using a variety of small "probe" molecules, with a conformer generator to account for side-chain flexibility. Applications to unliganded structures of 15 PPI target proteins show that the druggable sites comprise a cluster of binding hot spots, distinguishable from other regions of the protein due to their concave topology combined with a pattern of hydrophobic and polar functionality. This combination of properties confers on the hot spots a tendency to bind organic species possessing some polar groups decorating largely hydrophobic scaffolds. Thus, druggable sites at PPI are not simply sites that are complementary to particular organic functionality, but rather possess a general tendency to bind organic compounds with a variety of structures, including key side chains of the partner protein. Results also highlight the importance of conformational adaptivity at the binding site to allow the hot spots to expand to accommodate a ligand of drug-like dimensions. The critical components of this adaptivity are largely local, involving primarily low energy side-chain motions within 6 Å of a hot spot. The structural and physicochemical signature of druggable sites at PPI interfaces is sufficiently robust to be detectable from the structure of the unliganded protein, even when substantial conformational adaptation is required for optimal ligand binding.
尽管越来越多的小分子抑制剂能够破坏蛋白质-蛋白质相互作用（PPIs），但这些靶标的成药性的起源仍知之甚少。为了识别蛋白质-蛋白质界面中的可成药位点，我们将计算溶剂映射（使用各种小“探针”分子探索蛋白质表面）与构象生成器相结合，以考虑侧链的灵活性。对 15 个 PPI 靶蛋白的未配体结构的应用表明，可成药位点包括一组结合热点，由于其凹面拓扑结构以及疏水性和极性功能的模式，与蛋白质的其他区域区分开来。这种性质组合赋予热点结合具有一定极性基团修饰的大疏水性支架的有机物种的趋势。因此，PPI 上的可成药位点不仅仅是与特定有机功能互补的位点，而是具有与各种结构结合的有机化合物的一般趋势，包括伴侣蛋白的关键侧链。结果还强调了结合位点的构象适应性的重要性，以允许热点扩展以容纳类似药物尺寸的配体。这种适应性的关键组成部分在很大程度上是局部的，主要涉及热点周围 6 Å 内的低能量侧链运动。PPI 界面上可成药位点的结构和物理化学特征足够稳健，即使需要大量构象适应以获得最佳配体结合，也可以从未配体蛋白的结构中检测到。
