Huang Anzhong, Zhou Liang, Zhang Dawei, Yao Junliang, Zhang Yong
Department of General Surgery, Jinshan Hospital, Fudan University, Shanghai 201508, China.
Department of General Surgery, Jinshan Hospital, Fudan University, Shanghai 201508, China.
J Mol Graph Model. 2016 Nov;70:40-44. doi: 10.1016/j.jmgm.2016.09.007. Epub 2016 Sep 13.
Peptide therapeutics has been raised as an attractive approach for the treatment of breast cancer by targeting the oncogenic protein MDM2 that inactivates p53 tumor suppressor. Here, we performed molecular design of halogen bonding orthogonal to hydrogen bonding at the complex interface of MDM2 protein with its cognate peptide ligand to improve the peptide binding affinity and specificity. Crystal structure analysis, high-level quantum chemistry (QC) calculations and combined quantum mechanics/molecular mechanics (QM/MM) modeling revealed that halogen substitution at position 3 of the benzene moiety of peptide Phe3 residue can constitute a putative halogen bonding, which is shown to be geometrically perpendicular to and energetically independent of a native hydrogen bonding that share a common carbonyl oxygen acceptor. The designed halogen bonding was then validated by surface plasmon resonance (SPR) assays, that is, substitution with bromine at position 3 can considerably improve peptide affinity by ∼4-fold, but the peptide binding does not change substantially upon the bromine substitution at other positions of the Phe3 benzene moiety (the negative controls that are theoretically unable to form the halogen bonding), indicating that the orthogonal molecular interaction (OMI) system between the designed halogen bonding and native hydrogen bonding can co-work well at the complex interface of MDM2 protein with its halogenated peptide ligands.
通过靶向致癌蛋白MDM2（其可使p53肿瘤抑制因子失活），肽疗法已成为治疗乳腺癌的一种有吸引力的方法。在此，我们在MDM2蛋白与其同源肽配体的复合物界面处进行了与氢键正交的卤键分子设计，以提高肽的结合亲和力和特异性。晶体结构分析、高水平量子化学（QC）计算以及量子力学/分子力学（QM/MM）联合建模表明，肽Phe3残基苯环部分3位的卤素取代可构成一个假定的卤键，该卤键在几何上垂直于且在能量上独立于一个共享共同羰基氧受体的天然氢键。然后通过表面等离子体共振（SPR）分析验证了所设计的卤键，即3位用溴取代可使肽亲和力显著提高约4倍，但在Phe3苯环部分的其他位置进行溴取代（理论上无法形成卤键的阴性对照）时，肽结合没有实质性变化，这表明所设计的卤键与天然氢键之间的正交分子相互作用（OMI）系统可在MDM2蛋白与其卤化肽配体的复合物界面处协同良好工作。
