Molecular modelling and de novo fragment-based design of potential inhibitors of beta-tubulin gene of Necator americanus from natural products.
Molecular modelling and de novo fragment-based design of potential inhibitors of beta-tubulin gene of Necator americanus from natural products.
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DOI：
10.1016/j.imu.2021.100734
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发表时间：
2021-01-01
影响因子：
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通讯作者：
Wilson, Michael D
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文献类型：
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作者：
Agyapong, Odame;Asiedu, Seth O;Wilson, Michael D
对已知的钩虫药物即阿苯达唑和甲苯达唑的耐药性的出现及其降低的功效需要新药。化学多样性的天然产物提供了合理的模板，以增加钩虫药物的发现。本工作利用药物信息学技术预测非洲天然化合物ZINC 95486082，ZINC 95486052和euphohelionon作为钩虫美洲钩虫β微管蛋白基因的潜在抑制分子。针对β微管蛋白的同源建模结构筛选了3390种化合物的文库。使用根据受试者工作特征（ROC）曲线计算的0.714的可接受曲线下面积（AUC）验证了从AutoDock维纳获得的对接结果。所选的三种化合物具有良好的结合亲和力，并预测不会与耐药相关突变Phe 167、Glu 198和Phe 200形成相互作用。使用基于贝叶斯的技术预测这些化合物为驱虫剂，并将其特征分析为药物样。进一步的分子动力学模拟和MM-PBSA计算表明，化合物作为有前途的驱虫药物的领导者。新的关键残基，包括Leu 246，Asn 247和Asn 256也预测为结合。Euphohelionon被选为模板，用于标记为A1，A2，A3，A4和A5的五种化合物的从头片段设计;其中四种具有低于6的SAscore值，表示容易合成。所有五个从头分子牢固地对接在β微管蛋白的结合口袋中，与三个已知的抗性突变残基没有结合相互作用。A1、A2、A3、A4和A5的结合能分别为-8.2、-7.6、-7.3、-7.2和-6.8 kcal/mol。已鉴定的化合物可以作为未来有效驱虫剂设计的宝库。目前的研究致力于减轻钩虫病的负担，特别是使可用的分子有可能规避化学耐药性。
The emergence of drug resistance against the known hookworm drugs namely albendazole and mebendazole and their reduced efficacies necessitate the need for new drugs. Chemically diverse natural products present plausible templates to augment hookworm drug discovery. The present work utilized pharmacoinformatics techniques to predict African natural compounds ZINC95486082, ZINC95486052 and euphohelionon as potential inhibitory molecules of the hookworm Necator americanus beta tubulin gene. A library of 3390 compounds was screened against a homology-modelled structure of beta tubulin. The docking results obtained from AutoDock Vina was validated with an acceptable area under the curve (AUC) of 0.714 computed from the receiver operating characteristic (ROC) curve. The three selected compounds had favourable binding affinities and were predicted to form no interactions with the resistance-associated mutations Phe167, Glu198 and Phe200. The compounds were predicted as anthelmintics using a Bayesian-based technique and were pharmacologically profiled to be druglike. Further molecular dynamics simulations and MM-PBSA calculations showed the compounds as promising anthelmintic drug leads. Novel critical residues comprising Leu246, Asn247 and Asn256 were also predicted for binding. Euphohelionon was selected as a template for the de novo fragment-based design of five compounds labelled A1, A2, A3, A4 and A5; with four of them having SAscore values below 6, denoting easy synthesis. All the five de novo molecules docked firmly in the binding pocket of the beta tubulin with no binding interactions with the three known resistance mutation residues. Binding energies of -8.2, -7.6, -7.3, -7.2 and -6.8 kcal/mol were obtained for A1, A2, A3, A4 and A5, respectively. The identified compounds can serve as treasure troves from which future potent anthelmintics can be designed. The current study strives to assuage the hookworm disease burden, especially making available molecules with the potential to circumvent the chemoresistance.