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首页> 外文期刊>Journal of Medicinal Chemistry >A Molecular Basis for the Selectivity of Thiadiazole Urea Inhibitors with Stromelysin-1 and Gelatinase-A from Generalized Born Molecular Dynamics Simulations
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A Molecular Basis for the Selectivity of Thiadiazole Urea Inhibitors with Stromelysin-1 and Gelatinase-A from Generalized Born Molecular Dynamics Simulations

机译：广义出生的分子动力学模拟对噻二唑尿素抑制剂Stromelysin-1和明胶酶-A选择性的分子基础。

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Matrix metalloproteinases (MMPs) represent a potentially important class of therapeutic targets for the treatment of diseases such as cancer. Selective inhibition of MMPs will be required given the high sequence identity across the family and the discovery that individual MMPs also regulate the natural angiogenesis inhibitor angiostatin. In this study, we have used computational methods to model the selectivity for six thiadiazole urea inhibitors with stromelysin-1 and gelatinase-A, two homologous MMPs that have been implicated in breast cancer. From continuum Generalized Born molecular dynamics (GB-MD) and MM-GBSA analysis, we estimated ligand free energies of binding using 200 snapshots obtained from a short 40 ps simulation of the relevant protein-ligand complex. The MM-GBSA free energies, computed from the continuum GB-MD trajectories, show strong correlation with the experimental affinities (r~2 = 0.74); prior studies have employed explicit water MD simulations. Including estimates for changes in solute entropy in the binding calculations slightly diminishes the overall correlation with experiment (r~2 = 0.71). Notably, in every case, the simulation results correctly predict that a given ligand will bind selectively to stromelysin-1 over gelatinase-A which is gratifying given the high degree of structural homology between the two proteins. The increased selectivity for stromelysin-1 appears to be driven by (1) increased favorable van der Waals interactions, (2) increased favorable Coulombic interactions, and (3) decreased unfavorable total electrostatic energies (Coulombic plus desolvation).
机译：基质金属蛋白酶（MMP）代表了潜在的重要一类治疗靶标，用于治疗疾病（例如癌症）。鉴于家族中的高序列同一性以及发现单个MMP也可调节天然血管生成抑制剂血管抑制素，因此需要选择性抑制MMP。在这项研究中，我们已经使用计算方法来模拟六种噻二唑脲抑制剂与stromelysin-1和明胶酶-A的选择性，这两种基因已与乳腺癌相关。通过连续的广义博恩分子动力学（GB-MD）和MM-GBSA分析，我们使用200快照估算了结合的配体自由能，这些快照是通过对相关蛋白质-配体复合物进行的短40 ps模拟获得的。由连续的GB-MD轨迹计算得到的MM-GBSA自由能与实验亲和力有很强的相关性（r〜2 = 0.74）;先前的研究采用了显式的水MD模拟。在结合计算中包括溶质熵变化的估计值会稍微降低与实验的总体相关性（r〜2 = 0.71）。值得注意的是，在每种情况下，模拟结果均正确地预测给定的配体将通过明胶酶-A选择性地与基质溶菌素-1结合，考虑到这两种蛋白之间的高度结构同源性，这是令人满意的。对基质溶菌素-1选择性的增加似乎是由（1）有利的范德华相互作用增加，（2）有利的库伦相互作用增加和（3）不利的总静电能降低（库仑加去溶剂化）驱动的。

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