ABSTRACT

CREB binding protein (CBP) and its paralog E1A binding protein (p300) are related to the development of inflammatory diseases, cancers and other diseases, and have been potential targets for the treatment of human diseases. In this work, interaction mechanism of three small molecules E3T, E3H, and E3B with CBP was investigated by employing molecular dynamics (MD) simulations, principal component analysis (PCA), and molecular mechanics/generalized born surface area (MM-GBSA) method. The results indicate that inhibitor bindings cause the changes of movement modes and structural flexibility of CBP, and van der Waals interactions mostly drive associations of inhibitors with CBP. In the meantime, the results based on inhibitor-residue interactions not only show that eight residues of CBP can strongly interact with E3T, E3H and E3B but also verify that the CH-CH, CH-π, and π-π interactions are responsible for vital contributions in associations of E3T, E3H and E3B with CBP. In addition, the H-O radial distribution functions (RDFs) were computed to assess the stability of hydrogen bonding interactions between inhibitors and CBP, and the obtained information identifies several key hydrogen bonds playing key roles in bindings of E3T, E3H and E3B to CBP. Potential new inhibitors have been proposed.

摘要

CREB结合蛋白（CBP）及其旁系E1A结合蛋白（p300）与炎症性疾病，癌症和其他疾病的发展有关，已成为治疗人类疾病的潜在靶标。在这项工作中，通过分子动力学（MD）模拟，主成分分析（PCA）和分子力学/广义生表面积（MM-GBSA）方法研究了三种小分子E3T，E3H和E3B与CBP的相互作用机理。 。结果表明抑制剂结合引起CBP的运动方式和结构柔性的变化，范德华相互作用主要驱动抑制剂与CBP的缔合。同时，基于抑制剂-残基相互作用的结果不仅表明CBP的八个残基可以与E3T强烈相互作用，E3H和E3B，但也验证了CH-CH，CH-π和π-π相互作用是E3T，E3H和E3B与CBP关联的重要贡献。此外，计算了HO径向分布函数（RDFs）以评估抑制剂与CBP之间氢键相互作用的稳定性，并且获得的信息鉴定了在E3T，E3H和E3B与CBP的结合中起关键作用的几个关键氢键。已经提出了潜在的新抑制剂。所得信息鉴定了在E3T，E3H和E3B与CBP结合中起关键作用的几个关键氢键。已经提出了潜在的新抑制剂。所得信息鉴定了在E3T，E3H和E3B与CBP结合中起关键作用的几个关键氢键。已经提出了潜在的新抑制剂。