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利用药物再利用和虚拟筛选方法揭示用于皮肤利什曼病的新型精氨酸酶抑制剂

Unveiling Novel Arginase Inhibitors for Cutaneous Leishmaniasis Using Drug Repurposing and Virtual Screening Approaches.

作者信息

Barreto Eduarda Moreira, Pereira Gabriel Rodrigues Coutinho, Arêas Isadora de Salles, Fortes Júlia Mendes, Domingos Alessandra da Silva, Cabral Lucio Mendes, Rodrigues Carlos Rangel, de Souza Alessandra Mendonça Teles, Abrahim-Vieira Barbara de Azevedo

机构信息

Laboratory of Molecular Modeling & QSAR, Faculty of Pharmacy, Federal University of Rio de Janeiro, Rio de Janeiro, RJ, Brazil.

Laboratory of Industrial Pharmaceutical Technology, Faculty of Pharmacy, Federal University of Rio de Janeiro, Rio de Janeiro, RJ, Brazil.

出版信息

J Cell Biochem. 2025 Aug;126(8):e70060. doi: 10.1002/jcb.70060.


DOI:10.1002/jcb.70060
PMID:40847551
Abstract

Leishmaniasis is a neglected tropical disease with a significant global health burden, particularly in developing countries, where it accounts for approximately 1.6 million new infections annually. Current therapeutic options are limited by severe adverse effects, toxicity, and drug resistance, highlighting the urgent need for novel treatment strategies. Arginase from Leishmania spp. (LamARG) has been identified as a promising therapeutic target due to its pivotal role in parasite survival and proliferation. Drug repurposing offers a strategic advantage by accelerating the identification of new therapeutics with established safety profiles, as demonstrated by repurposed agents such as miltefosine, amphotericin B, and paromomycin. This study aimed to identify FDA-approved drugs with inhibitory potential against LamARG, leveraging structure- and ligand-based computational approaches. A three-dimensional model of LamARG was constructed through comparative modeling, followed by the compilation of known inhibitors from the literature. Molecular docking analyzed their binding interactions, generating pharmacophore hypotheses. These models were validated and applied for virtual screening of FDA-approved compounds from the e-Drug 3D database. Hits identified through pharmacophore-based screening were further evaluated using molecular docking and molecular dynamics simulations to elucidate their binding modes and stability within the catalytic site of LamARG. Our findings indicate that Dabigatran exhibits strong binding affinity and key interactions within the active site of LamARG, suggesting its potential as a viable therapeutic candidate. With strong binding affinity, oral bioavailability, and a well-established safety profile, Dabigatran emerges as a promising repurposed drug against cutaneous leishmaniasis, offering a novel, patient-friendly therapeutic option to overcome treatment limitations and resistance challenges.

摘要

利什曼病是一种被忽视的热带疾病,给全球健康带来重大负担,在发展中国家尤为如此,每年约有160万新感染病例。目前的治疗选择受到严重不良反应、毒性和耐药性的限制,凸显了对新型治疗策略的迫切需求。利什曼原虫属的精氨酸酶(LamARG)因其在寄生虫存活和增殖中的关键作用而被确定为一个有前景的治疗靶点。药物再利用通过加速识别具有既定安全概况的新疗法提供了战略优势,如米替福新、两性霉素B和巴龙霉素等再利用药物所证明的那样。本研究旨在利用基于结构和配体的计算方法,识别对LamARG具有抑制潜力的美国食品药品监督管理局(FDA)批准的药物。通过比较建模构建了LamARG的三维模型,随后从文献中汇编了已知抑制剂。分子对接分析了它们的结合相互作用,生成了药效团假设。这些模型经过验证后,用于对e-Drug 3D数据库中FDA批准的化合物进行虚拟筛选。通过基于药效团的筛选确定的命中物,使用分子对接和分子动力学模拟进一步评估,以阐明它们在LamARG催化位点内的结合模式和稳定性。我们的研究结果表明,达比加群在LamARG的活性位点内表现出很强的结合亲和力和关键相互作用,表明其作为一种可行治疗候选物的潜力。达比加群具有很强的结合亲和力、口服生物利用度和完善的安全概况,成为一种有前景的针对皮肤利什曼病的再利用药物,为克服治疗限制和耐药性挑战提供了一种新颖、患者友好的治疗选择。

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本文引用的文献

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J Biomol Struct Dyn. 2023

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