针对京沙努尔森林病病毒包膜蛋白的潜在药理抑制剂的计算探索

Pharmaceuticals Pub Date : 2024-07-03 DOI:10.3390/ph17070884
Sharanappa Achappa, N. Aldabaan, S. Desai, Uday M. Muddapur, I. Shaikh, M. Mahnashi, Abdullateef A. Alshehri, B. A. Mannasaheb, A. Khan
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引用次数: 0

摘要

目前针对Kyasanur森林疫病病毒(KFDV)的疫苗接种策略存在局限性,这凸显了对有效抗病毒疗法的迫切需要,同时也强调了通过默克药物设计探索新型治疗方法的极端重要性。由 KFDV 引起的 Kyasanur 森林病是一种蜱媒疾病,死亡率为 3-5%,年发病率为 400 至 500 例。在感染的早期阶段,包膜蛋白通过促进宿主与病毒之间的相互作用发挥着至关重要的作用。这项研究的目标是开发针对包膜蛋白的有效抗病毒药物,以破坏病毒与宿主之间的相互作用。为此,我们通过分子建模技术对包膜蛋白的三维结构进行了建模和完善,随后通过从头设计和药效筛选设计了配体,并进行了 ADMET 分析。前五名候选配体进行了几何优化和分子对接。值得注意的是,根据计算模型预测,化合物 L4(SA28)和 L3(CNP0247967)与包膜蛋白的结合亲和力分别为 -8.91 和 -7.58 kcal/mol。在 200 ns 的分子动力学模拟中,这两种化合物都表现出了稳定性,包膜蛋白 L3 和 L4 复合物的 MM-GBSA 结合自由能值分别为 -85.26 ± 4.63 kcal/mol 和 -66.60 ± 2.92 kcal/mol。根据计算预测,这两种化合物都有可能作为候选药物,通过靶向包膜蛋白来控制宿主与病毒之间的相互作用。通过体外实验进行进一步验证将补充本研究的结果。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Computational Exploration of Potential Pharmacological Inhibitors Targeting the Envelope Protein of the Kyasanur Forest Disease Virus
The limitations of the current vaccination strategy for the Kyasanur Forest Disease virus (KFDV) underscore the critical need for effective antiviral treatments, highlighting the crucial importance of exploring novel therapeutic approaches through in silico drug design. Kyasanur Forest Disease, caused by KFDV, is a tick-borne disease with a mortality of 3–5% and an annual incidence of 400 to 500 cases. In the early stage of infection, the envelope protein plays a crucial role by facilitating host–virus interactions. The objective of this research is to develop effective antivirals targeting the envelope protein to disrupt the virus–host interaction. In line with this, the 3D structure of the envelope protein was modeled and refined through molecular modeling techniques, and subsequently, ligands were designed via de novo design and pharmacophore screening, yielding 12 potential hits followed by ADMET analysis. The top five candidates underwent geometry optimization and molecular docking. Notably, compounds L4 (SA28) and L3 (CNP0247967) are predicted to have significant binding affinities of −8.91 and −7.58 kcal/mol, respectively, toward the envelope protein, based on computational models. Both compounds demonstrated stability during 200 ns molecular dynamics simulations, and the MM-GBSA binding free-energy values were −85.26 ± 4.63 kcal/mol and −66.60 ± 2.92 kcal/mol for the envelope protein L3 and L4 complexes, respectively. Based on the computational prediction, it is suggested that both compounds have potential as drug candidates for controlling host–virus interactions by targeting the envelope protein. Further validation through in-vitro assays would complement the findings of the present in silico investigations.
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