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首页> 外文期刊>Journal of Biomolecular Structure and Dynamics >Developing Hispolon-based novel anticancer therapeutics against human (NF-kP) using in silico approach of modelling, docking and protein dynamics
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Developing Hispolon-based novel anticancer therapeutics against human (NF-kP) using in silico approach of modelling, docking and protein dynamics

机译：使用模拟，对接和蛋白质动力学的硅方法，在硅（NF-KP）中促进综合的新型抗癌治疗措施

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摘要

Hispolon is a polyphenolic compound derived from black hoof mushroom (Phellinus linteus) or shaggy bracket mushroom {Inonotus hispidus) which induces the inhibition of cancer-promoting nuclear factor-kappa beta (NF-kP) complex. To develop more potent lead molecules with enhanced anticancer efficiency, the mechanism of hispolon-mediated nuclear factor-KP inhibition has been investigated by molecular modelling and docking. Ten derivatives of hispolon (DRG1-10) have been developed by pharmacophore-based design with a view to enhance the anticancer efficacy. Hispolon and its derivatives were further screened for different pharmacological parameters like binding free energy, drug likeliness, absorption-digestion-metabolism-excretion (ADME), permeability, mutagenicity, toxicity and inhibitory concentration 50 (IC50) to find a potent lead molecule. Based on pharmacological validation, comparative molecular dynamics (MD) simulations have been performed for three lead molecules: Hispolon, DRG2 and DRG7 complexed with human NF-kP up to 50 ns. By analysing different factors like root mean square deviation (RMSD), root mean square fluctuation (RMSF), radius of gyration (Rg), solvent-accessible surface area (SASA) and principal component analysis (PCA), Gibb's free energy plots DRG2 have more binding efficiency compared to hispolon and DRG7. In RMSD plot, hispolon-bound NF-kP has the most deviation within a range between 0.125 and 0.45 nm, and DRG2-bound complex showed the range between 0.125 and 0.25 nm. The residues of NF-kP responsible for hydrophobic interactions with ligand, e.g. Met469, Leu522 and Cys533, have the lowest fluctuation values in DRG2-bound complex. The average Rg fluctuation for DRG2-bound NF-kP has been recorded under 2.025 nm for most of the simulation time which is much less compared to hispolon and DRG7. Gibb's free energy plots also define the highest stability of DRG2-bound NF-kP.
机译：Hisogolon是一种衍生自黑蹄蘑菇（Phellinus Linteus）或毛茸茸的支架蘑菇（Inonotus Hispidus）的多酚化合物，其诱因抑制癌症促进的核因子-Kappaβ（NF-KP）复合物。为了开发具有增强的抗癌效率的更有效的铅分子，通过分子建模和对接研究了Hispolon介导的核因子-KP抑制的机制。由基于Pharmocophore的设计制定的HISOLON（DRG1-10）的十个衍生物，以增强抗癌效果。进一步筛选Hispolon及其衍生物的不同药理参数，如结合自由能，药物可能性，吸收 - 消化 - 代谢排泄（ADME），渗透性，突变度，毒性和抑制浓度50（IC 50），以找到有效的铅分子。基于药理学验证，对三种铅分子进行了比较分子动力学（MD）模拟：Hispolon，DRG2和DRG7与人NF-KP络合至50ns。通过分析像根均方偏差（RMSD）等不同因素，根均方波动（RMSF），环状半径（RG），溶剂可接近的表面积（SASA）和主成分分析（PCA），GIBB的自由能量绘图DRG2具有与Hispolon和DRG7相比的更具结合效率。在RMSD图中，Hisogolon-Landed NF-KP在0.125和0.45nm之间的范围内具有最大的偏差，并且DRG2结合的复合物显示在0.125和0.25nm之间的范围内。 NF-KP的残留物负责与配体的疏水相互作用，例如， MET469，LEU522和CYS533，具有DRG2绑定的复合物中最低的波动值。对于大多数模拟时间，DRG2结合NF-KP的平均RG波动已记录在2.025nm下，与HIRSOLON和DRG7相比的大部分模拟时间。 GIBB的自由能量图也限定了DRG2结合NF-KP的最高稳定性。

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