Sinefungin analogs targeting VP39 methyltransferase as potential anti-monkeypox therapeutics: a multi-step computational approach

IF 3.9 2区化学 Q2 CHEMISTRY, APPLIED

Molecular Diversity Pub Date : 2024-05-04 DOI:10.1007/s11030-024-10875-z

Amr S. Abouzied, Bader Huwaimel, Saad Alqarni, Kareem M. Younes, Rakan E. Alshammari, Abdulkarim H. Alshammari, Wadaah F. Algharbi, Akram M. Elkashlan

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Abstract

The increasing spread of the Monkeypox virus (MPXV) presents a significant public health challenge, emphasising the urgent requirement for effective treatments. Our study focuses on the VP39 Methyltransferase enzyme of MPXV as a critical target for therapy. By utilising virtual screening, we investigated natural compounds with structural similarities to sinefungin, a broad-acting MTase inhibitor. From an initial set of 177 compounds, we identified three promising compounds—CNP0346326, CNP0343532, and CNP008361, whose binding scores were notably close to that of sinefungin. These candidates bonded strongly to the VP39 enzyme, hinting at a notable potential to impede the virus. Our rigorous computational assays, including re-docking, extended molecular dynamics simulations, and energetics analyses, validate the robustness of these interactions. The data paint a promising picture of these natural compounds as front-runners in the ongoing race to develop MPXV therapeutics and set the stage for subsequent empirical trials to refine these discoveries into actionable medical interventions.

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以 VP39 甲基转移酶为靶点的松香菌素类似物作为潜在的抗猴头痘疗法：一种多步骤计算方法。

猴痘病毒（MPXV）的传播日益猖獗，对公共卫生构成了重大挑战，因此迫切需要有效的治疗方法。我们的研究重点是将 MPXV 的 VP39 甲基转移酶作为治疗的关键靶点。通过虚拟筛选，我们研究了与宽效 MT 酶抑制剂正银霉素结构相似的天然化合物。从最初的 177 种化合物中，我们发现了三种有前景的化合物--CNP0346326、CNP0343532 和 CNP008361，它们的结合得分与正鱼腥苷非常接近。这些候选化合物与 VP39 酶的结合力很强，表明它们具有显著的抑制病毒的潜力。我们进行了严格的计算测定，包括重新对接、扩展分子动力学模拟和能量分析，验证了这些相互作用的稳健性。这些数据为这些天然化合物描绘了一幅充满希望的图景，它们将成为正在进行的 MPXV 治疗药物开发竞赛中的领跑者，并为后续的经验性试验奠定了基础，以便将这些发现完善为可操作的医疗干预措施。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

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;