Cheminformatics Modeling of Closantel Analogues for Treating River Blindness
semanticscholar(2020)
摘要
Onchocerciasis (also known as river
blindness) is a neglected tropical
disease caused by the Onchocerca volvulus
parasitic nematode. Currently, the only approved drug for treating this disease
is ivermectin, which is a broad-spectrum antiparasitic agent. However, signs of
resistance towards ivermectin have started to emerge. New therapeutic agents
are thus urgently needed. The OvCHT1 chitinase enzyme from O. volvulus has been established as a relevant biological target
for combatting river blindness. The veterinary anthelmintic drug closantel has
been found to be a potent, micro-molar OvCHT1 inhibitor. Herein, we
investigated the chemical space of closantel and all its synthesized analogues,
focusing on the analysis of their potential binding modes towards OvCHT1. First,
we conducted an unsupervised hierarchical clustering to group highly similar
analogues and explore structure-activity relationships. Second, we conducted a
structure-based molecular docking to predict and study the binding modes of all
57 closantel analogues in the active site of OvCHT1. Third, we screened more
than 4 million lead-like compounds from the ZINC library to identify other structurally
similar ligands that could potentially bind to OvCHT1. The cheminformatics analysis of the closantel analogues illustrated
how minor structural changes in closantel analogues can impact their OvCHT1
activity.
更多查看译文
AI 理解论文
溯源树
样例
生成溯源树,研究论文发展脉络
Chat Paper
正在生成论文摘要