Chagas disease, caused by the protozoan Trypanosoma cruzi, remains a significant global health burden, particularly in Latin America, where millions are at risk. This disease predominantly affects socioeconomically vulnerable populations, aggravating economic inequality, marginalization, and low political visibility. Despite extensive research, effective treatments are still lacking, partly due to the complex biology of the parasite and its infection mechanisms. This study focuses on TcP21, a novel 21 kDa protein secreted by extracellular amastigotes, which has been implicated in T. cruzi infection via an alternative infective pathway. Although the potential of TcP21 for understanding Chagas disease is promising, further exploration is necessary, particularly in identifying potential binding sites on its surface. Computational tools offer a versatile and effective strategy for preliminary binding site assessment, facilitating a more cost-efficient allocation of experimental resources. In this study, we employed three independent computational approaches─mixed solvent molecular dynamics simulations (MSMD), fragment-based molecular docking, and pharmacophore model docking coupled with molecular dynamics simulations─to identify potential binding sites and provide comprehensive insights into TcP21. The three methodologies converged on a common site located on the external surface of the protein, characterized by key residues such as GLU55, ASP52, VAL70, ILE62, and TRP77. The protonated amino, acetamido, and phenyl groups of the pharmacophore probe were consistently observed to interact with the site via a network of salt bridges, hydrogen bonds, charge-charge interactions, and alkyl-π interactions, suggesting these groups play a significant role in ligand binding. This study does not aim to propose specific therapeutic hits but to highlight a still unknown and unexplored protein involved in T. cruzi cell invasion. In this regard, given the strong correlation between the three distinct approaches used for mapping, we consider this study offers valuable insights for further research into P21 and its role in Chagas disease.

中文翻译：

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使用集成的混合溶剂分子动力学方法探索查加斯病蛋白 TcP21 中的结合位点。


由原生动物克氏锥虫引起的美洲锥虫病仍然是一个重大的全球健康负担，尤其是在拉丁美洲，那里有数百万人处于危险之中。这种疾病主要影响社会经济弱势群体，加剧经济不平等、边缘化和政治知名度低。尽管进行了广泛的研究，但仍然缺乏有效的治疗方法，部分原因是寄生虫及其感染机制的复杂性。本研究侧重于 TcP21，这是一种由细胞外无鞭毛细胞分泌的新型 21 kDa 蛋白，通过另一种感染途径与克氏锥虫感染有关。尽管 TcP21 在理解美洲锥虫病方面的潜力很有希望，但还需要进一步探索，特别是在确定其表面的潜在结合位点方面。计算工具为初步结合位点评估提供了一种通用且有效的策略，有助于更经济高效地分配实验资源。在本研究中，我们采用了三种独立的计算方法——混合溶剂分子动力学模拟 （MSMD）、基于片段的分子对接和药效团模型对接结合分子动力学模拟——来识别潜在的结合位点并提供对 TcP21 的全面见解。这三种方法汇聚在位于蛋白质外表面的共同位点上，其特征是 GLU55、ASP52、VAL70、ILE62 和 TRP77 等关键残基。一致观察到药效团探针的质子化氨基、乙酰氨基和苯基通过盐桥、氢键、电荷-电荷相互作用和烷基-π 相互作用的网络与位点相互作用，表明这些基团在配体结合中起重要作用。 本研究的目的不是提出特定的治疗命中，而是强调一种仍然未知且未探索的蛋白质，该蛋白质参与克氏锥虫细胞侵袭。在这方面，鉴于用于绘图的三种不同方法之间的强相关性，我们认为这项研究为进一步研究 P21 及其在美洲锥虫病中的作用提供了有价值的见解。