Department of Pharmaceutical Chemistry, University of California, San Francisco, California, USA.
J Chem Inf Model. 2010 Sep 27;50(9):1561-73. doi: 10.1021/ci100214a.
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 docking reliability with minimal cost to calculation time and may be readily incorporated into any physics-based docking program.
在基于结构的新配体筛选中，分子对接算法必须快速对多种构型的大量分子进行评分，既要考虑配体与受体的相互作用，又要考虑其与溶剂的竞争相互作用。在这里，我们探讨了一种用于分子对接的基于上下文的配体去溶剂化评分项。我们将每个配体原子的广义 Born 有效 Born 半径与部分去溶剂化相关联，然后使用该分数来缩放全转移自由能的原子分解。部分去溶剂化在评分网格上预先计算，通过对配体原子附近受体的体积进行数值积分，并按距离加权。为了测试这种方法的性能，我们针对 40 个 DUD 靶点的性质匹配诱饵对配体进行对接。与原始全转移自由能惩罚相比，与完全忽略去溶剂化相比，基于上下文的去溶剂化可以更好地富集配体，尽管这种改善是适度的。更引人注目的是，新方法提高了跨受体类型的对接性能。因此，完全忽略去溶剂化对带电位点效果最好，而完全去溶剂化对中性位点的惩罚效果很好，而基于上下文的更正确的配体去溶剂化在这两种类型的靶点上都具有竞争力。该方法还能可靠地区分配体和高电荷分子，而完全忽略去溶剂化在这种情况下效果不佳。由于这种基于上下文的配体去溶剂化可以预先计算，因此它可以提高对接的可靠性，而计算时间的成本最小，并且可以很容易地整合到任何基于物理的对接程序中。
