Department of Pharmaceutical Sciences, University of Maryland School of Pharmacy, 20 Penn Street HSF II, Baltimore, Maryland 21201, USA.
J Chem Inf Model. 2011 Apr 25;51(4):877-96. doi: 10.1021/ci100462t. Epub 2011 Apr 1.
The applicability of a computational method, Site Identification by Ligand Competitive Saturation (SILCS), to identify regions on a protein surface with which different types of functional groups on low-molecular weight inhibitors interact is demonstrated. The method involves molecular dynamics (MD) simulations of a protein in an aqueous solution of chemically diverse small molecules from which probability distributions of fragments types, termed FragMaps, are obtained. In the present application, SILCS simulations are performed with an aqueous solution of 1 M benzene and propane to map the affinity pattern of the protein for aromatic and aliphatic functional groups. In addition, water hydrogen and oxygen atoms serve as probes for hydrogen-bond donor and acceptor affinity, respectively. The method is tested using a set of 7 proteins for which crystal structures of complexes with several high affinity inhibitors are known. Good agreement is obtained between FragMaps and the positions of chemically similar functional groups in inhibitors as observed in the X-ray crystallographic structures. Quantitative capabilities of the SILCS approach are demonstrated by converting FragMaps to free energies, termed Grid Free Energies (GFE), and showing correlation between the GFE values and experimental binding affinities. For proteins for which ligand decoy sets are available, GFE values are shown to typically score the crystal conformation and conformations similar to it more favorable than decoys. Additionally, SILCS is tested for its ability to capture the subtle differences in ligand affinity across homologous proteins, information which may be of utility toward specificity-guided drug design. Taken together, our results show that SILCS can recapitulate the known location of functional groups of bound inhibitors for a number of proteins, suggesting that the method may be of utility for rational drug design.
本文展示了一种计算方法（配体竞争饱和的位点鉴定（SILCS））在鉴定蛋白质表面与低分子量抑制剂的不同类型功能基团相互作用的区域中的适用性。该方法涉及在含有化学多样性小分子的水溶液中进行蛋白质的分子动力学（MD）模拟，从中可以获得片段类型的概率分布，称为 FragMaps。在本应用中，使用 1 M 苯和丙烷的水溶液进行 SILCS 模拟，以绘制蛋白质对芳族和脂肪族功能基团的亲和力模式。此外，水的氢和氧原子分别用作氢键供体和受体亲和力的探针。该方法使用一组 7 种蛋白质进行了测试，这些蛋白质的晶体结构已知与几种高亲和力抑制剂复合物。FragMaps 与抑制剂中化学相似的功能基团的位置之间得到了很好的一致性，这与 X 射线晶体结构中观察到的一致。通过将 FragMaps 转换为自由能（称为网格自由能（GFE）），并显示 GFE 值与实验结合亲和力之间的相关性，展示了 SILCS 方法的定量能力。对于有配体诱饵集的蛋白质，GFE 值通常会显示出对晶体构象及其相似构象的评分比诱饵更有利。此外，还测试了 SILCS 捕捉同源蛋白质中配体亲和力细微差异的能力，这些信息可能对特异性导向药物设计有用。总之，我们的结果表明，SILCS 可以重现许多蛋白质中结合抑制剂的功能基团的已知位置，这表明该方法可能对合理的药物设计有用。
