Testing inhomogeneous solvation theory in structure-based ligand discovery
Testing inhomogeneous solvation theory in structure-based ligand discovery
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DOI：
10.1073/pnas.1703287114
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发表时间：
2017-08-15
影响因子：
11.1
通讯作者：
Shoichet, Brian K.
中科院分区：
文献类型：
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作者：
Balius, Trent E.;Fischer, Marcus;Shoichet, Brian K.
结合位点的水在配体识别过程中经常被取代，但在基于结构的配体发现中通常被忽视。非均相溶剂化理论（IST）已成为处理这种效应的流行理论，但尚未在原子分辨率的对照实验中得到验证。为此，我们转向了这种方法的基于网格的版本，GIST，它很容易在分子对接中实现。虽然该术语仅在回顾性配体富集中适度改善对接，但它可以在不破坏性能的情况下添加。因此，我们转向大型文库的前瞻性对接，以研究GIST对配体发现、几何形状和水结构的影响，这些影响非常适合于探索这些术语。虽然有或没有GIST术语的顶级停靠分子经常重叠，但许多配体被有意义地优先或不优先；其中一些被选中进行测试。实验中，被GIST优先排序的13/14个分子确实结合了，而被GIST优先排序的分子没有一个被观察到结合。测定了9个晶体配合物。其中6个配体的几何形状与GIST预测的一致，其中一个没有GIST项的姿势是错误的，三个晶体学姿势与两个预测不同。值得注意的是，在一个结构中，一个具有高GIST位移惩罚的有序水分子被观察到停留在原地。尽管其影响的幅度可能很小，而且其对药物结合位点的影响值得进一步的对照研究，但纳入这个水置换项可以大大提高对接屏幕的命中率和配体几何形状。
Binding-site water is often displaced upon ligand recognition, but is commonly neglected in structure-based ligand discovery. Inhomogeneous solvation theory (IST) has become popular for treating this effect, but it has not been tested in controlled experiments at atomic resolution. To do so, we turned to a grid-based version of this method, GIST, readily implemented in molecular docking. Whereas the term only improves docking modestly in retrospective ligand enrichment, it could be added without disrupting performance. We thus turned to prospective docking of large libraries to investigate GIST's impact on ligand discovery, geometry, and water structure in a model cavity site well-suited to exploring these terms. Although top-ranked docked molecules with and without the GIST term often overlapped, many ligands were meaningfully prioritized or deprioritized; some of these were selected for testing. Experimentally, 13/14 molecules prioritized by GIST did bind, whereas none of the molecules that it deprioritized were observed to bind. Nine crystal complexeswere determined. In six, the ligand geometry corresponded to that predicted by GIST, for one of these the pose without the GIST term was wrong, and three crystallographic poses differed fromboth predictions. Notably, in one structure, an ordered water molecule with a high GIST displacement penalty was observed to stay in place. Inclusion of this water-displacement term can substantially improve the hit rates and ligand geometries from docking screens, although the magnitude of its effects can be small and its impact in drug binding sites merits further controlled studies.