Tetteh Cyril, Andoh Mensah Andy, Ampomah Bernice, Oppong Mahmood B, Lartey Michael, Donkor Paul Owusu, Opuni Kwabena Fm, Adutwum Lawrence A
Department of Pharmaceutical Chemistry, School of Pharmacy, University of Ghana, Accra, Ghana.
Department of Pharmacognosy and Herbal Medicine, School of Pharmacy, University of Ghana, Accra, Ghana.
Bioinform Biol Insights. 2025 Sep 4;19:11779322251368252. doi: 10.1177/11779322251368252. eCollection 2025.
There is a need to improve the discovery of new drugs for neglected tropical diseases (NTDs), as the lack of financial incentives has slowed their development. Currently, ivermectin and moxidectin are used in the management of onchocerciasis. We present a proof-of-concept study based on computational methods to find anti-infectives that can be repurposed or serve as lead compounds for onchocerciasis. A combination of exploratory data analysis, machine learning (ML), and molecular docking studies was used to evaluate 58 anti-infective agents. Out of the 58 test drugs, 14 were predicted by at least 5 ML models to be potentially useful in managing onchocerciasis. Molecular docking studies with the 14 predicted drugs using glutamate-gated chloride channel, a known target of ivermectin, an onchocerciasis drug, yielded good results. Cridanimod, diminazene, and vandetanib were the top 3 agents showing the highest binding affinities of -7.8, -7.2, and 7.1 kcal/mol, respectively, higher than the native ligand glutamate, which has a value of -4.5 kcal/mol. The binding interactions of these agents also showed overlaps with that of doramectin and pyrvinium agents that have demonstrated activity against onchocerciasis and ivermectin, the gold standard for onchocerciasis management. This study highlights the potential of cridanimod, diminazene, and vandetanib as promising candidates for developing new treatments for onchocerciasis.
由于缺乏经济激励措施减缓了被忽视热带病（NTDs）新药的研发进程，因此有必要改进这类药物的发现。目前，伊维菌素和莫西菌素被用于治疗盘尾丝虫病。我们开展了一项基于计算方法的概念验证研究，以寻找可重新利用或用作盘尾丝虫病先导化合物的抗感染药物。通过探索性数据分析、机器学习（ML）和分子对接研究相结合的方法，对58种抗感染药物进行了评估。在这58种受试药物中，至少有5种ML模型预测14种药物可能对治疗盘尾丝虫病有用。使用盘尾丝虫病药物伊维菌素的已知靶点谷氨酸门控氯离子通道，对这14种预测药物进行分子对接研究，结果良好。克立莫德、地美硝唑和凡德他尼是结合亲和力最高的前3种药物，分别为-7.8、-7.2和-7.1千卡/摩尔，高于天然配体谷氨酸的-4.5千卡/摩尔。这些药物的结合相互作用也与多拉菌素和吡维铵的结合相互作用有重叠，多拉菌素和吡维铵已证明对盘尾丝虫病有活性，而伊维菌素是盘尾丝虫病治疗的金标准。这项研究突出了克立莫德、地美硝唑和凡德他尼作为开发盘尾丝虫病新疗法的有前景候选药物的潜力。
