Determinants of Activity at Human Toll-like Receptors 7 and 8: Quantitative Structure鈥揂ctivity Relationship (QSAR) of Diverse Heterocyclic Scaffolds

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• 作者：Euna Yoo ; Deepak B. Salunke ; Diptesh Sil ; Xiaoqiang Guo ; Alex C. D. Salyer ; Alec R. Hermanson ; Manoj Kumar ; Subbalakshmi S. Malladi ; Rajalakshmi Balakrishna ; Ward H. Thompson ; Hiromi Tanji ; Umeharu Ohto ; Toshiyuki Shimizu ; Sunil A. David
• 刊名：Journal of Medicinal Chemistry
• 出版年：2014
• 出版时间：October 9, 2014
• 年：2014
• 卷：57
• 期：19
• 页码：7955-7970
• 全文大小：927K
• ISSN：1520-4804

文摘

Toll-like receptor (TLR) 7 and 8 agonists are potential vaccine adjuvants, since they directly activate APCs and enhance Th1-driven immune responses. Previous SAR investigations in several scaffolds of small molecule TLR7/8 activators pointed to the strict dependence of the selectivity for TLR7 vis-脿-vis TLR8 on the electronic configurations of the heterocyclic systems, which we sought to examine quantitatively with the goal of developing 鈥渉euristics鈥?to define structural requisites governing activity at TLR7 and/or TLR8. We undertook a scaffold-hopping approach, entailing the syntheses and biological evaluations of 13 different chemotypes. Crystal structures of TLR8 in complex with the two most active compounds confirmed important binding interactions playing a key role in ligand occupancy and biological activity. Density functional theory based quantum chemical calculations on these compounds followed by linear discriminant analyses permitted the classification of inactive, TLR8-active, and TLR7/8 dual-active compounds, confirming the critical role of partial charges in determining biological activity.