Synthetic inhibitor leads of human tropomyosin receptor kinase A (hTrkA),RSC Medicinal Chemistry

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Synthetic inhibitor leads of human tropomyosin receptor kinase A (hTrkA)
RSC Medicinal Chemistry ( IF 4.1 ) Pub Date : 2020-01-10 , DOI: 10.1039/c9md00554d
Govindan Subramanian ₁ , Rajendran Vairagoundar ₁ , Scott J Bowen ₁ , Nicole Roush ₁ , Theresa Zachary ₁ , Christopher Javens ₁ , Tracey Williams ₁ , Ann Janssen ₁ , Andrea Gonzales ₁

Affiliation

In silico virtual screening followed by in vitro biochemical, biophysical, and cellular screening resulted in the identification of distinctly different hTrkA kinase domain inhibitor scaffolds. X-ray structural analysis of representative inhibitors bound to hTrkA kinase domain defined the binding mode and rationalized the mechanism of action. Preliminary assessment of the sub-type selectivity against the closest hTrkB isoform, and early ADME guided the progression of select inhibitor leads in the screening cascade. The possibility of the actives sustaining to known hTrkA resistance mutations assessed in silico offers initial guidance into the required multiparametric lead optimization to arrive at a clinical candidate.

中文翻译：

人原肌球蛋白受体激酶 A (hTrkA) 的合成抑制剂先导化合物

计算机虚拟筛选以及体外生化、生物物理和细胞筛选导致鉴定出明显不同的h TrkA 激酶结构域抑制剂支架。与h TrkA 激酶结构域结合的代表性抑制剂的 X 射线结构分析定义了结合模式并合理化了作用机制。对最接近的h TrkB 同工型的亚型选择性的初步评估和早期 ADME 指导了筛选级联中选择抑制剂先导化合物的进展。通过计算机评估，活性物质维持已知h TrkA 耐药突变的可能性为获得临床候选药物所需的多参数先导化合物优化提供了初步指导。

更新日期：2020-01-10

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