Kozakov Dima, Hall David R, Jehle Stefan, Luo Lingqi, Ochiana Stefan O, Jones Elizabeth V, Pollastri Michael, Allen Karen N, Whitty Adrian, Vajda Sandor
Department of Biomedical Engineering, Boston University, Boston, MA 02215;
Acpharis Inc., Holliston, MA 01746;
Proc Natl Acad Sci U S A. 2015 May 19;112(20):E2585-94. doi: 10.1073/pnas.1501567112. Epub 2015 Apr 27.
Fragment-based drug discovery (FBDD) relies on the premise that the fragment binding mode will be conserved on subsequent expansion to a larger ligand. However, no general condition has been established to explain when fragment binding modes will be conserved. We show that a remarkably simple condition can be developed in terms of how fragments coincide with binding energy hot spots--regions of the protein where interactions with a ligand contribute substantial binding free energy--the locations of which can easily be determined computationally. Because a substantial fraction of the free energy of ligand binding comes from interacting with the residues in the energetically most important hot spot, a ligand moiety that sufficiently overlaps with this region will retain its location even when other parts of the ligand are removed. This hypothesis is supported by eight case studies. The condition helps identify whether a protein is suitable for FBDD, predicts the size of fragments required for screening, and determines whether a fragment hit can be extended into a higher affinity ligand. Our results show that ligand binding sites can usefully be thought of in terms of an anchor site, which is the top-ranked hot spot and dominates the free energy of binding, surrounded by a number of weaker satellite sites that confer improved affinity and selectivity for a particular ligand and that it is the intrinsic binding potential of the protein surface that determines whether it can serve as a robust binding site for a suitably optimized ligand.
基于片段的药物发现（FBDD）基于这样一个前提：片段的结合模式在随后扩展为更大的配体时将保持不变。然而，尚未确立一般条件来解释何时片段结合模式会保持不变。我们表明，可以根据片段与结合能热点（即蛋白质中与配体相互作用贡献大量结合自由能的区域，其位置可通过计算轻松确定）的重合情况来建立一个非常简单的条件。由于配体结合自由能的很大一部分来自与能量上最重要热点中的残基相互作用，即使去除配体的其他部分，与该区域充分重叠的配体部分仍将保留其位置。这一假设得到了八个案例研究的支持。该条件有助于确定一种蛋白质是否适合FBDD，预测筛选所需片段的大小，并确定命中的片段是否可以扩展为具有更高亲和力的配体。我们的结果表明，配体结合位点可以有效地根据一个锚定位点来考虑，该锚定位点是排名最高的热点，主导结合自由能，周围有一些较弱的卫星位点，这些位点赋予对特定配体更好的亲和力和选择性，并且蛋白质表面的内在结合潜力决定了它是否可以作为经过适当优化的配体的强大结合位点。
