Jiangsu Key Laboratory of New Drug Research and Clinical Pharmacy, Xuzhou Medical University, 209 Tongshan Road, Xuzhou 221004, China.
College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China.
Int J Mol Sci. 2024 Sep 28;25(19):10477. doi: 10.3390/ijms251910477.
c-Src is involved in multiple signaling pathways and serves as a critical target in various cancers. Growing evidence suggests that prolonging a drug's residence time (RT) can enhance its efficacy and selectivity. Thus, the development of c-Src antagonists with longer residence time could potentially improve therapeutic outcomes. In this study, we employed molecular dynamics simulations to explore the binding modes and dissociation processes of c-Src with antagonists characterized by either long or short RTs. Our results reveal that the long RT compound DAS-DFGO-I (DFGO) occupies an allosteric site, forming hydrogen bonds with residues E310 and D404 and engaging in hydrophobic interactions with residues such as L322 and V377. These interactions significantly contribute to the long RT of DFGO. However, the hydrogen bonds between the amide group of DFGO and residues E310 and D404 are unstable. Substituting the amide group with a sulfonamide yielded a new compound, DFOGS, which exhibited more stable hydrogen bonds with E310 and D404, thereby increasing its binding stability with c-Src. These results provide theoretical guidance for the rational design of long residence time c-Src inhibitors to improve selectivity and efficacy.
c-Src 参与多种信号通路，是多种癌症的关键靶点。越来越多的证据表明，延长药物的停留时间（RT）可以提高其疗效和选择性。因此，开发具有更长停留时间的 c-Src 拮抗剂可能会改善治疗效果。在这项研究中，我们使用分子动力学模拟来探索具有长或短 RT 的拮抗剂与 c-Src 的结合模式和解离过程。我们的结果表明，长 RT 化合物 DAS-DFGO-I（DFGO）占据变构位点，与残基 E310 和 D404 形成氢键，并与残基 L322 和 V377 等形成疏水相互作用。这些相互作用对 DFGO 的长 RT 有显著贡献。然而，DFGO 酰胺基团与 E310 和 D404 之间的氢键不稳定。将酰胺基团替换为磺酰胺得到了一种新的化合物 DFOGS，它与 E310 和 D404 形成更稳定的氢键，从而提高了与 c-Src 的结合稳定性。这些结果为合理设计具有长停留时间的 c-Src 抑制剂以提高选择性和疗效提供了理论指导。
