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潜在的Mcl-1基抑制剂的体设计

Naser Faraji^1,2, Norelle L Daly³, Seyed Shahriar Arab⁴

¹Department of Medical Nanotechnology, Faculty of Advanced Medical Sciences, Tabriz University of Medical Sciences, Daneshgah Street, Tabriz, Iran.

Journal of molecular modeling

|March 19, 2024

概括

这项研究使用生物信息学和模拟设计了一种针对Mcl-1的螺旋,用于癌症治疗. 模拟5显示了增加的螺旋性和Mcl-1结合亲和力,表明作为抗癌药物候选药物的潜力.

科学领域:

计算化学和结构生物学
药物的发现和开发.
生物信息学和类设计

背景情况:

针对骨髓细胞白血病-1 (Mcl-1) 的Bcl-2相互作用亡媒介 (BIM) 衍生是潜在的抗癌药物.
螺旋性对于功能至关重要,但当前增强螺旋性的方法存在缺点.
这项研究的目的是设计一种更螺旋性的,没有非自然的残留物或接头.

研究的目的:

使用in silico方法设计一种新型的,高度螺旋性的,以Mcl-1为目标.
通过增强螺旋性和Mcl-1结合,提高BIM衍生的抗癌潜力.
为了避免与现有的改策略相关的缺点.

主要方法:

使用ApInAPDB和PRALINE确定了序列.
使用Cham finder,GOR,神经网络和Chou-Fasman算法来预测二级结构.
使用分子动力学模拟 (100 ns) 和MM-PBSA来评估对Mcl-1和Bcl-xL的结合亲和力.

主要成果:

在类型5 (A4fE和A2eE) 中的突变显示出与Mcl-1结合的偏好.
循环二元化证实,模拟5的螺旋性从18%增加到34%.
MM-PBSA显示了对Mcl-1进行向的类比5的特异性.

结论:

应用的in silico策略可以指导未来的设计.
模拟5显示了增强的Mcl-1向和螺旋性,表明作为抗癌治疗的潜力.
进一步的体外和体内评价是相似5作为候选药物的必要.

关键词:

细胞灭亡 (apoptosis) 是一种死亡的过程.这是一种BIM.在Mcl-1中.分子动态模拟分子动态模拟的设计的设计

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