Imam Mohammed A, Alandijany Thamir A, Felemban Hashim R, Attar Roba M, Faizo Arwa A, Gattan Hattan S, Dwivedi Vivek Dhar, Azhar Esam I
Department of Medical Microbiology and Parasitology, Qunfudah Faculty of Medicine, Umm Al-Qura University, Al-Qunfudah, 21961, Saudi Arabia.
Special Infectious Agents Unit-BSL3, King Fahd Medical Research Center, King Abdulaziz University, 21362, Jeddah, Saudi Arabia.
Mol Divers. 2025 Aug;29(4):2899-2917. doi: 10.1007/s11030-024-10975-w. Epub 2024 Sep 4.
The dengue virus is a major global health hazard responsible for an estimated 390 million diseases yearly. This study focused on identifying cyclopeptide inhibitors for envelope structural proteins E, NS1, NS3, and NS5. Additionally, 5579 cyclopeptides were individually screened against the four target proteins using a machine learning-based quantitative structure-activity relationship model. Subsequently, the best 10 cyclopeptides from each protein were selected for molecular docking with their corresponding proteins. Moreover, the protein-peptide complexes with the highest affinity were subjected to a 100-ns molecular dynamics simulation. The protein-protein complexes exhibited superior structural stability and binding interactions. Based on the results of the MD simulation analyses, which included checking values for Root Mean Square Deviation, Root Mean Square Fluctuation, Principal Component Analysis (PCA), free energy landscapes, and energetic components, it was found that NS5-CP03714 complex is more stable and has stronger binding interactions than NS3-CP02054. PCA and free energy landscape plots have confirmed the higher conformational stability of NS5-CP03714. Analysis of the energetic components revealed that NS5-CP03714 (total binding energy = - 47.19 kcal/mol) exhibits more favorable interaction energies and overall binding energy compared to NS3-CP02054 (total binding energy = - 27.36 kcal/mol), suggesting a stronger and more stable formation of the complex. In addition, the drug-target network of two specific peptides (CP02950 and CP05582) and their associated target proteins were analyzed. This analysis revealed valuable information about their ability to target several proteins and their potential for broad-spectrum activity. Additional experimental investigations are necessary to validate these computational results and assess the efficacy of identified peptide inhibitors in biological systems.
登革热病毒是一种主要的全球健康危害，每年估计导致3.9亿人患病。本研究重点在于鉴定针对包膜结构蛋白E、NS1、NS3和NS5的环肽抑制剂。此外，使用基于机器学习的定量构效关系模型，针对这四种靶蛋白分别筛选了5579种环肽。随后，从每种蛋白中选出最佳的10种环肽，与相应蛋白进行分子对接。此外，对具有最高亲和力的蛋白 - 肽复合物进行了100纳秒的分子动力学模拟。蛋白质 - 蛋白质复合物表现出卓越的结构稳定性和结合相互作用。基于分子动力学模拟分析的结果，包括检查均方根偏差、均方根波动、主成分分析（PCA）、自由能景观和能量成分的值，发现NS5 - CP03714复合物比NS3 - CP02054更稳定，且具有更强的结合相互作用。PCA和自由能景观图证实了NS5 - CP03714具有更高的构象稳定性。对能量成分的分析表明，与NS3 - CP02054（总结合能 = - 27.36千卡/摩尔）相比，NS5 - CP03714（总结合能 = - 47.19千卡/摩尔）表现出更有利的相互作用能和整体结合能，表明复合物形成更强且更稳定。此外，分析了两种特定肽（CP02950和CP05582）及其相关靶蛋白的药物 - 靶标网络。该分析揭示了它们靶向多种蛋白的能力及其广谱活性潜力的有价值信息。需要进行额外的实验研究来验证这些计算结果，并评估所鉴定肽抑制剂在生物系统中的功效。
