Computational Chemistry Department, Shanghai ChemPartner Co., Ltd., Shanghai, China.
Chemistry Department, Shanghai ChemPartner Co., Ltd., Shanghai, China.
PLoS One. 2022 Apr 22;17(4):e0260565. doi: 10.1371/journal.pone.0260565. eCollection 2022.
TLR7 and TLR8 are key members of the Toll-like receptor family, playing crucial roles in the signaling pathways of innate immunity, and thus become attractive therapeutic targets of many diseases including infections and cancer. Although TLR7 and TLR8 show a high degree of sequence homology, their biological response to small molecule binding is very different. Aiming to understand the mechanism of selective profiles of small molecule modulators against TLR7 and TLR8, we carried out molecular dynamic simulations on three imidazoquinoline derivatives bound to the receptors separately. They are Resiquimod (R), Hybrid-2 (H), and Gardiquimod (G), selective agonists of TLR7 and TLR8. Our MD trajectories indicated that in the complex of TLR7-R and TLR7-G, the two chains forming the TLR7 dimer tended to remain "open" conformation, while the rest systems maintained in the closed format. The agonists R, H, and G developed conformational deviation mainly on the aliphatic tail. Furthermore, we attempted to quantify the selectivity between TLR7 and TLR8 by binding free energies via MM-GBSA method. It showed that the three selected modulators were more favorable for TLR7 than TLR8, and the ranking from the strongest to the weakest was H, R and G, aligning well with experimental data. In the TLR7, the flexible and hydrophobic aliphatic side chain of H has stronger van der Waals interactions with V381 and F351 but only pick up interaction with one amino acid residue i.e. Y353 of TLR8. Unsurprisingly, the positively charged side chain of G has less favorable interaction with I585 of TLR7 and V573 of TLR8 explaining G is weak agonist of both TLR7 and TLR8. All three imidazoquinoline derivatives can form stable hydrogen bonds with D555 of TLR7 and the corresponding D543 of TLR8. In brief, the set of total 400ns MD studies sheds light on the potential selectivity mechanisms of agonists towards TLR7 and TLR8, indicating the van der Waals interaction as the driving force for the agonists binding, thus provides us insights for designing more potent and selective modulators to cooperate with the hydrophobic nature of the binding pocket.
TLR7 和 TLR8 是 Toll 样受体家族的关键成员，在先天免疫信号通路中发挥着重要作用，因此成为包括感染和癌症在内的许多疾病的有吸引力的治疗靶点。尽管 TLR7 和 TLR8 显示出高度的序列同源性，但它们对小分子结合的生物学反应却大不相同。为了了解小分子调节剂对 TLR7 和 TLR8 选择性特征的机制，我们分别对三种结合受体的咪唑并喹啉衍生物进行了分子动力学模拟。它们是瑞喹莫德（R）、杂合子-2（H）和加地喹胺（G），分别是 TLR7 和 TLR8 的选择性激动剂。我们的 MD 轨迹表明，在 TLR7-R 和 TLR7-G 复合物中，形成 TLR7 二聚体的两条链倾向于保持“开放”构象，而其余系统保持闭合形式。激动剂 R、H 和 G 主要在脂肪族尾部发生构象偏差。此外，我们试图通过 MM-GBSA 方法通过结合自由能来量化 TLR7 和 TLR8 之间的选择性。结果表明，三种选定的调节剂对 TLR7 比 TLR8 更有利，从最强到最弱的排序为 H、R 和 G，与实验数据吻合良好。在 TLR7 中，H 的柔性和疏水性脂肪族侧链与 V381 和 F351 具有更强的范德华相互作用，但仅与 TLR8 的一个氨基酸残基 Y353 相互作用。毫不奇怪，G 的带正电荷侧链与 TLR7 的 I585 和 TLR8 的 V573 的相互作用较差，这解释了 G 是 TLR7 和 TLR8 的弱激动剂。三种咪唑并喹啉衍生物都可以与 TLR7 的 D555 和 TLR8 的相应 D543 形成稳定的氢键。总之，这一系列总共 400ns 的 MD 研究阐明了激动剂对 TLR7 和 TLR8 的潜在选择性机制，表明范德华相互作用是激动剂结合的驱动力，从而为我们设计更有效和选择性的调节剂提供了见解，以配合结合口袋的疏水性。
