Aljohani Majed S, Hu Xiche
Department of Chemistry and Biochemistry, University of Toledo, Toledo, OH 43606, USA.
Department of Chemistry, College of Science Yanbu, Taibah University, Yanbu 30799, Saudi Arabia.
Molecules. 2025 Feb 21;30(5):1007. doi: 10.3390/molecules30051007.
Diaryl ureas (DU) are a cornerstone scaffold in organic and medicinal chemistry, celebrated for their unique structural attributes and broad range of biomedical applications. Their therapeutic reach has broadened beyond kinase inhibition in cancer therapy to encompass diverse mechanisms, including modulation of chromatin remodeling complexes, interference with developmental signaling pathways, and inhibition of stress-activated protein kinases in inflammatory disorders. A critical element in the rational design and optimization of DU-based therapeutics is a detailed understanding of their molecular recognition by target proteins. In this study, we employed a multi-tiered computational approach to investigate the molecular determinants of DU-protein interactions. A large-scale data mining of the Protein Data Bank resulted in an in-house dataset of 158 non-redundant, high-resolution crystal structures of DU-protein complexes. This dataset serves as the basis for a systematic analysis of nonbonded interactions, including hydrogen bonding, salt bridges, π-π stacking, CH-π, cation-π, and XH-π interactions (X = OH, NH, SH). Advanced electronic structure calculations at the B2PLYP/def2-QZVP level are applied to quantify the energetic contributions of these interactions and their roles in molecular recognition of diaryl ureas in their target proteins. The study led to the following findings: central to the molecular recognition of diaryl ureas in proteins are nonbonded π interactions-predominantly CH-π and π-π stacking-that synergize with hydrogen bonding to achieve high binding affinity and specificity. Aromatic R groups in diaryl ureas play a pivotal role by broadening the interaction footprint within hydrophobic protein pockets, enabling energetically favorable and diverse binding modes. Comparative analyses highlight that diaryl ureas with aromatic R groups possess a more extensive and robust interaction profile than those with non-aromatic counterparts, emphasizing the critical importance of nonbonded π interactions in molecular recognition. These findings enhance our understanding of molecular recognition of diaryl ureas in proteins and provide valuable insights for the rational design of diaryl ureas as potent and selective inhibitors of protein kinases and other therapeutically significant proteins.
二芳基脲（DU）是有机化学和药物化学中的一种基础骨架，因其独特的结构特性和广泛的生物医学应用而备受赞誉。它们的治疗范围已从癌症治疗中的激酶抑制扩展到多种机制，包括调节染色质重塑复合物、干扰发育信号通路以及抑制炎症性疾病中的应激激活蛋白激酶。基于二芳基脲的治疗药物合理设计和优化的一个关键要素是详细了解它们与靶蛋白的分子识别。在本研究中，我们采用了多层次计算方法来研究二芳基脲与蛋白质相互作用的分子决定因素。对蛋白质数据库进行大规模数据挖掘，得到了一个包含158个非冗余、高分辨率二芳基脲 - 蛋白质复合物晶体结构的内部数据集。该数据集作为系统分析非键相互作用的基础，包括氢键、盐桥、π-π堆积、CH-π、阳离子-π和XH-π相互作用（X = OH、NH、SH）。在B2PLYP/def2-QZVP水平上进行的先进电子结构计算用于量化这些相互作用的能量贡献及其在二芳基脲在其靶蛋白中的分子识别中的作用。该研究得出了以下发现：蛋白质中二芳基脲分子识别的核心是非键π相互作用——主要是CH-π和π-π堆积——它们与氢键协同作用以实现高结合亲和力和特异性。二芳基脲中的芳香族R基团通过扩大疏水蛋白质口袋内的相互作用区域发挥关键作用，从而实现能量上有利且多样的结合模式。比较分析突出表明，具有芳香族R基团的二芳基脲比具有非芳香族对应物的二芳基脲具有更广泛和更强健的相互作用谱，强调了非键π相互作用在分子识别中的至关重要性。这些发现增进了我们对二芳基脲在蛋白质中分子识别的理解，并为合理设计作为蛋白激酶和其他具有治疗意义蛋白质的有效和选择性抑制剂的二芳基脲提供了有价值的见解。
