Rapid Context-Dependent Ligand Desolvation in Molecular Docking
Rapid Context-Dependent Ligand Desolvation in Molecular Docking
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DOI：
10.1021/ci100214a
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发表时间：
2010-09-01
影响因子：
5.6
通讯作者：
Shoichet, Brian K.
中科院分区：
文献类型：
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作者：
Mysinger, Michael M.;Shoichet, Brian K.
在基于结构的新配体筛选中，分子对接算法必须考虑配体与受体的相互作用以及与溶剂的竞争相互作用，快速对多种构型的许多分子进行评分。在这里，我们探索了一个上下文相关的配体去溶度计分术语，用于分子对接。我们将每个配体原子的广义玻恩有效玻恩半径与分数解溶度联系起来，然后用这个分数来标度整个转移自由能的逐个原子分解。分数去溶度是在记分网格上通过对配体原子近端的受体体积进行数值积分来预先计算的，按距离加权。为了测试这种方法的性能，我们将配体与属性匹配的诱饵对接在40个无用目标上。与原始的完全转移自由能惩罚相比，与完全忽略去溶解相比，上下文相关的去溶解更好地丰富了配体，尽管改善幅度不大。更引人注目的是，新方法提高了不同受体类型的对接性能。因此，尽管完全忽略去溶解对带电部位最好，而过度惩罚完全去溶解对中性部位很好，但物理上更正确的上下文依赖的配体去溶解在这两种类型的靶子中都是有竞争力的。该方法还可靠地区分了配体和高电荷态分子，在高电荷态下，忽略去溶解效果很差。由于这种上下文相关的配体去溶度可以预先计算，它以最小的计算时间成本提高了计时可靠性，并且可以很容易地合并到任何基于物理的对接程序中。
In structure-based screens for new ligands, a molecular docking algorithm must rapidly score many molecules in multiple configurations, accounting for both the ligand's interactions with receptor and its competing interactions with solvent. Here we explore a context-dependent ligand desolvation scoring term for molecular docking. We relate the Generalized-Born effective Born radii for every ligand atom to a fractional desolvation and then use this fraction to scale an atom-by-atom decomposition of the full transfer free energy. The fractional desolvation is precomputed on a scoring grid by numerically integrating over the volume of receptor proximal to a ligand atom, weighted by distance. To test this method's performance, we dock ligands versus property-matched decoys over 40 DUD targets. Context-dependent desolvation better enriches ligands compared to both the raw full transfer free energy penalty and compared to ignoring desolvation altogether, though the improvement is modest. More compellingly, the new method improves docking performance across receptor types. Thus, whereas entirely ignoring desolvation works best for charged sites and overpenalizing with full desolvation works well for neutral sites, the physically more correct context-dependent ligand desolvation is competitive across both types of targets. The method also reliably discriminates ligands from highly charged molecules, where ignoring desolvation performs poorly. Since this context-dependent ligand desolvation may be precalculated, it improves clocking reliability with minimal cost to calculation time and may be readily incorporated into any physics-based docking program.