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Identifying MurI uncompetitive inhibitors by correlating decomposed binding energies with bioactivity

机译：通过将分解的结合能与生物活性相关鉴定Muri非竞争力抑制剂

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The glutamate racemase (MurI) is essential for Helicobacter pylori (H. pylori) cell wall biosynthesis. In this work, we report a new method that correlates decomposed binding free energies with MurI inhibition based upon the data from pyrazolopyrimidinedione series MurI uncompetitive inhibitors. With the molecular mechanics/generalized Born surface areas (MM/GBSA) approach, we were able to decompose the binding interaction into van der Waals, electrostatic, and polar solvation surfaces. The decomposed binding energies were correlated with MurI inhibitory activity with partial least squares regression (PLSR). Hence, the method is termed MM/GBSA-PLSR. The non-cross-validation (R-2) and leave-one-out crossvalidation (LOOCV) (Q(2)) correlation coefficients of the 3D-QSAR model are 0.962 and 0.822, respectively. The external testing yields a predicted correlation coefficient (R-pred (2)) of 0.817. This study demonstrated that the activity-contribution fractions from the three types of ligand-receptor interactions are 29.5% from van der Waal interactions, 38.2% from electrostatic interactions, and 32.3% from polar solvation interactions. Comparing with molecular field analysis (CoMFA) and comparative molecular similarity index analysis (CoMSIA), we find that the CoMFA/CoMSIA steric interaction fields can be interpreted as the MM/GBSA-PLSR van der Waals interactions; CoMFA/CoMSIA electrostatic and H-bond acceptor/donor interaction fields can be interpreted as the MM/GBSA-PLSR electrostatic interactions. However, there is no explicit association between MM/GBSA-PLSR solvation interactions (polar or non-polar) and CoMFA/CoMSIA fields. It is worth noting that the solvation interaction is important for ligand design. Moreover, MM/GBSA-PLSR maps the decomposed binding interactions on to pharmacophore surfaces (van der Waals, electrostatic, and polar solvation surfaces) to aid drug design.
机译：谷氨酸外周血酶（MURI）对于幽门螺杆菌（H.幽门螺杆菌）细胞壁生物合成至关重要。在这项工作中，我们报告了一种新的方法，这些方法基于来自吡唑啉嘧啶胺系列Muri非竞争剂抑制剂的数据来相关的分解与Muri抑制。利用分子力学/广义出生的表面积（MM / GBSA）方法，我们能够将结合相互作用分解为范德华，静电和极性溶剂化表面。分解的结合能与Muri抑制活性与部分最小二乘回归（PLSR）相关。因此，该方法被称为MM / GBSA-PLSR。 3D-QSAR模型的非交叉验证（R-2）和休留次外交叉验证（LOOCV）（Q（2））分别为0.962和0.822。外部测试产生0.817的预测相关系数（R-PEAT（2））。本研究证明，来自三种配体 - 受体相互作用的活性贡献级分是van der腰部相互作用的29.5％，距静电相互作用38.2％，与极性溶剂化相互作用的32.3％。与分子场分析（COMFA）和比较分子相似性指数分析（COMSIA）相比，我们发现COMFA / COMSIA间隔相互作用场可以被解释为MM / GBSA-PLSR范德华相互作用; COMFA / COMSIA静电和H键受体/供体相互作用场可以解释为MM / GBSA-PLSR静电相互作用。但是，MM / GBSA-PLSR溶剂化相互作用（极性或非极性）和COMFA / COMSIA字段之间没有明确关联。值得注意的是，溶剂化相互作用对于配体设计很重要。此外，MM / GBSA-PLSR将分解的结合相互作用映射到药仔植物表面（van der Waals，静电和极性溶剂化表面）以帮助药物设计。

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  • 来源
    《RSC Advances》 |2015年第51期|共10页
  • 作者

    Le Xiu; Gu Qiong; Xu Jun;

  • 作者单位

    Sun Yat Sen Univ Sch Pharmaceut Sci Res Ctr Drug Discovery Guangzhou 510006 Guangdong Peoples R China;

    Sun Yat Sen Univ Sch Pharmaceut Sci Res Ctr Drug Discovery Guangzhou 510006 Guangdong Peoples R China;

    Sun Yat Sen Univ Sch Pharmaceut Sci Res Ctr Drug Discovery Guangzhou 510006 Guangdong Peoples R China;

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