From antibiotic to antiviral: computational screening reveals a multi-targeting antibiotic from Streptomyces spp. against Nipah virus fusion proteins.

IF 3.9 2区 化学 Q2 CHEMISTRY, APPLIED
Nyzar Mabeth O Odchimar, Mark Andrian B Macalalad, Fredmoore L Orosco
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引用次数: 0

Abstract

Nipah Virus is a re-emerging zoonotic paramyxovirus that poses a significant threat to both swine industry and human health. The pursuit of potential antiviral agents with both preventive and therapeutic properties holds promise for targeting such viruses. To expedite this search, leveraging computational biology is essential. Streptomyces is renowned for its capacity to produce large and diverse metabolites with promising bioactivities. In the current study, we conducted a comprehensive structure-based virtual screening of 6524 Streptomyces spp. metabolites sourced from the StreptomeDB database to evaluate their potential inhibitory effects on three Nipah virus fusion (NiVF) protein conformations: NiVF pre-fusion 1-mer (NiVF-1mer), pre-fusion 3-mer (NiVF-3mer), and NiVF post-fusion (NiVF-PoF). Prior to virtual screening, the drug-likeness of Streptomyces spp. compounds was profiled using ADMET properties. From the 913 ADMET-filtered compounds, the subsequent targeted and confirmatory blind docking analysis revealed that S896 or virginiamycin M1, a known macrolide antibiotic, showed a maximum binding affinity with the NiVF proteins, suggesting a multi-targeting inhibitory property. In addition, the 200-ns molecular dynamics simulation and MM/PBSA analyses revealed stable and strong binding affinity between the NiVF-S896 complexes, indicating favorable interactions between S896 and the target proteins. These findings suggest the potential of virginiamycin M1, an antibiotic, as a promising multi-targeting antiviral drug. However, in vitro and in vivo experimental validations are necessary to assess their safety and efficacy.

Abstract Image

从抗生素到抗病毒药物:计算筛选揭示了链霉菌针对尼帕病毒融合蛋白的多靶点抗生素。
尼帕病毒是一种重新出现的人畜共患副粘病毒,对养猪业和人类健康都构成了重大威胁。寻找具有预防和治疗特性的潜在抗病毒药物是针对此类病毒的希望所在。要加快这一探索,利用计算生物学是必不可少的。链霉菌因其能够产生大量具有良好生物活性的多种代谢产物而闻名于世。在本研究中,我们对来自 StreptomeDB 数据库的 6524 种链霉菌代谢物进行了全面的基于结构的虚拟筛选,以评估它们对三种尼帕病毒融合(NiVF)蛋白构象的潜在抑制作用:NiVF前融合1-mer(NiVF-1mer)、前融合3-mer(NiVF-3mer)和NiVF后融合(NiVF-PoF)。在进行虚拟筛选之前,利用 ADMET 特性分析了链霉菌属化合物的药物亲和性。从 913 个 ADMET 筛选出的化合物中,随后进行的定向和确认性盲法对接分析表明,S896 或维吉尼霉素 M1(一种已知的大环内酯类抗生素)与 NiVF 蛋白的结合亲和力最大,表明其具有多靶点抑制特性。此外,200ns分子动力学模拟和MM/PBSA分析表明,NiVF-S896复合物之间的结合亲和力稳定而强大,表明S896与靶蛋白之间存在良好的相互作用。这些发现表明,抗生素维吉尼霉素 M1 有可能成为一种前景广阔的多靶点抗病毒药物。然而,要评估其安全性和有效性,还需要进行体外和体内实验验证。
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来源期刊
Molecular Diversity
Molecular Diversity 化学-化学综合
CiteScore
7.30
自引率
7.90%
发文量
219
审稿时长
2.7 months
期刊介绍: Molecular Diversity is a new publication forum for the rapid publication of refereed papers dedicated to describing the development, application and theory of molecular diversity and combinatorial chemistry in basic and applied research and drug discovery. The journal publishes both short and full papers, perspectives, news and reviews dealing with all aspects of the generation of molecular diversity, application of diversity for screening against alternative targets of all types (biological, biophysical, technological), analysis of results obtained and their application in various scientific disciplines/approaches including: combinatorial chemistry and parallel synthesis; small molecule libraries; microwave synthesis; flow synthesis; fluorous synthesis; diversity oriented synthesis (DOS); nanoreactors; click chemistry; multiplex technologies; fragment- and ligand-based design; structure/function/SAR; computational chemistry and molecular design; chemoinformatics; screening techniques and screening interfaces; analytical and purification methods; robotics, automation and miniaturization; targeted libraries; display libraries; peptides and peptoids; proteins; oligonucleotides; carbohydrates; natural diversity; new methods of library formulation and deconvolution; directed evolution, origin of life and recombination; search techniques, landscapes, random chemistry and more;
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