Discovery of Trypanosoma cruzi Carbonic Anhydrase Inhibitors by a Combination of Ligand- and Structure-Based Virtual Screening

Trypanosoma cruzi carbonic anhydrase
(TcCA) has emerged as a promising therapeutic target
for the treatment of Chagas disease. In this study, a sequential virtual
screening strategy was employed to identify potential TcCA inhibitors. The workflow consisted of ligand-based virtual screening
applied to diverse chemical libraries, followed by target-based molecular
docking to refine the selection of compounds. Six candidates were
selected for their in vitro evaluation against both
the enzyme and the parasite. All of them confirmed inhibitory activity
against TcCA, with three exhibiting Kis in the nanomolar or submicromolar range. Among these,
Nitrofurantoin demonstrated significant inhibitory activity, with
a Ki of 93 nM against TcCA and EC50 of 14.82 μM against T.
cruzi trypomastigotes. These findings suggest that
Nitrofurantoin is a promising lead compound for further optimization
and highlight the therapeutic potential of TcCA as
a drug target in Chagas disease.

克氏锥虫（Trypanosoma cruzi）碳酸酐酶（TcCA）已成为治疗恰加斯病（Chagas disease）的极具潜力的治疗靶点。本研究采用序贯虚拟筛选策略，旨在鉴定潜在的TcCA抑制剂。该筛选流程首先针对多样化化学库开展基于配体的虚拟筛选，随后通过基于靶点的分子对接对候选化合物进行精筛。最终选取6种候选化合物，分别开展针对该酶与寄生虫的体外评价。结果显示，所有候选化合物均对TcCA具有抑制活性，其中3种的抑制常数（Ki）处于纳摩尔或亚微摩尔级别。在这3种活性化合物中，呋喃妥因（Nitrofurantoin）表现出显著的抑制效果：其对TcCA的Ki值为93 nM，对克氏锥虫锥鞭毛体（T. cruzi trypomastigotes）的半数有效浓度（EC₅₀）为14.82 μM。本研究结果表明，呋喃妥因是一种极具开发价值的先导化合物，可用于后续的结构优化；同时也进一步证实了TcCA作为恰加斯病治疗靶点的临床转化潜力。