Comparative Analysis of Pharmacophore Features and Quantitative Structure-Activity Relationships for CD38 Covalent and Non-covalent Inhibitors
Comparative Analysis of Pharmacophore Features and Quantitative Structure-Activity Relationships for CD38 Covalent and Non-covalent Inhibitors
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DOI：
10.1111/cbdd.12606
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发表时间：
2015-12-01
影响因子：
3
通讯作者：
Liu, Zhenming
中科院分区：
文献类型：
--
作者：
Zhang, Shuang;Xue, Xiwen;Liu, Zhenming
在过去的十年里，我们的团队和合作伙伴相继报道了数百种CD38共价和非共价抑制剂的发现、合成和评价，但对于CD38抑制剂的合理设计，仍缺乏系统的基于结构的指导。在这里，我们对CD38抑制剂的药效团特征和定量构效关系进行了比较分析。结果发现，关键残基与共价/非共价CD38抑制剂之间的主要相互作用包括(I)与Glu226和Trp125残基的氢键和疏水相互作用，(Ii)与带正电荷残基Arg127区域的静电或氢键相互作用，以及(Iii)与Trp189残基的疏水相互作用。对于共价抑制剂，除了与Glu226残基的共价作用外，与Arg127残基的静电相互作用也是必要的，同时还可以检测到与Trp125和Trp189残基的另一种氢/非键相互作用。通过SYBYL多拟合比对函数，最好的CoMFA和CoMSIA与CD38型共价抑制剂的交叉验证相关系数(Q(2))分别为0.564和0.571，未交叉验证的相关系数(r(2))分别为0.967和0.971。CD38非共价抑制剂根据其化学骨架可分为五类，其中Glu226、Trp189和Trp125残基是与CD38结合的非共价抑制剂所必需的，Ser126、Arg127、Asp155、Thr221和Phe222残基也是重要的。与F12类似物交叉验证的相关系数(Q(2))分别为0.469和0.454，非交叉验证的相关系数(r(2))分别为0.814和0.819。
In the past decade, the discovery, synthesis, and evaluation for hundreds of CD38 covalent and non-covalent inhibitors has been reported sequentially by our group and partners; however, a systematic structure-based guidance is still lacking for rational design of CD38 inhibitor. Here, we carried out a comparative analysis of pharmacophore features and quantitative structure-activity relationships for CD38 inhibitors. The results uncover that the essential interactions between key residues and covalent/non-covalent CD38 inhibitors include (i) hydrogen bond and hydrophobic interactions with residues Glu226 and Trp125, (ii) electrostatic or hydrogen bond interaction with the positively charged residue Arg127 region, and (iii) the hydrophobic interaction with residue Trp189. For covalent inhibitors, besides the covalent effect with residue Glu226, the electrostatic interaction with residue Arg127 is also necessary, while another hydrogen/nonbonded interaction with residues Trp125 and Trp189 can also be detected. By means of the SYBYL multifit alignment function, the best CoMFA and CoMSIA with CD38 covalent inhibitors presented cross-validated correlation coefficient values (q(2)) of 0.564 and 0.571, and non-cross-validated values (r(2)) of 0.967 and 0.971, respectively. The CD38 non-covalent inhibitors can be classified into five groups according to their chemical scaffolds, and the residues Glu226, Trp189, and Trp125 are indispensable for those non-covalent inhibitors binding to CD38, while the residues Ser126, Arg127, Asp155, Thr221, and Phe222 are also important. The best CoMFA and CoMSIA with the F12 analogues presented cross-validated correlation coefficient values (q(2)) of 0.469 and 0.454, and noncross-validated values (r(2)) of 0.814 and 0.819, respectively.