揭开病毒药物点:一种基于深度学习的方法,用于识别潜在的结合部位
Petr Popov1,2, Roman Kalinin3, Pavel Buslaev4
1Tetra-d, Rheinweg 9, Schaffhausen, 8200, Switzerland.
Briefings in bioinformatics
|December 19, 2023
概括
计算方法在SARS-CoV-2尖端蛋白上确定了一个新的药物标. 当这个网站被准时,可以通过稳定状蛋白在不活跃的构造中来抑制病毒的进入,从而帮助COVID-19药物发现.
科学领域:
- 结构生物学是结构生物学.
- 计算病毒学计算病毒学.
- 药物发现 药物发现
背景情况:
- 由于COVID-19的流行,需要快速确定有效的抗病毒疗法.
- 为像SARS-CoV-2这样的病毒选择可行的药物标是药物开发中的一个重要瓶.
- 计算方法可以通过分析病毒蛋白质结构来加快潜在药物标的识别.
研究的目的:
- 开发和验证基于结构和深度学习的计算方法,用于识别病毒蛋白上脆弱的药物结合部位.
- 将这种方法应用于SARS-CoV-2尖端糖蛋白 (S),以找到新的治疗点.
- 调查针对已识别的网站以抑制病毒进入的潜力.
主要方法:
- 利用基于结构和深度学习的方法,整合了蛋白质动态,结合点可访问性,可变性和药物作用机制.
- 将该方法应用于SARS-CoV-2尖端蛋白,专注于受体结合域.
- 执行了尖端蛋白-药物复合体的分子动力学模拟,并使用基于伪型病毒的测定方法验证了结果.
主要成果:
- 在SARS-CoV-2尖端蛋白上确定了一个新的,特定于形状和寡合体的,不含甘氨酸的结合部位,位于受体结合域附近.
- 分子动力学模拟表明,与该位点结合的候选药物将平衡转移到不活跃的尖峰形状.
- 一种伪型病毒测定确定了在微分子度下抑制病毒进入的命中化合物.
结论:
- 已确定的结合部位代表了开发SARS-CoV-2抑制剂的有希望的全性标.
- 准这个部位可能会阻止与人类ACE2受体相互作用的尖端蛋白所需的构造过渡.
- 这种计算策略有效地识别了针对COVID-19药物开发的病毒蛋白的脆弱区域.
相关概念视频
01:49Conserved Binding Sites
4.2K
Many proteins’ biological role depends on their interactions with their ligands, small molecules that bind to specific locations on the protein known as ligand-binding sites. Ligand-binding sites are often conserved among homologous proteins as these sites are critical for protein function.
Binding sites are often located in large pockets, and if their location on a protein’s surface is unknown, it can be predicted using various approaches. The energetic method computationally...
Binding sites are often located in large pockets, and if their location on a protein’s surface is unknown, it can be predicted using various approaches. The energetic method computationally...
4.2K
01:26Drug Discovery: Overview
7.9K
Drug discovery is a multifaceted process involving extensive screening, testing, and optimization of lead compounds to identify potential new drugs for therapeutic use. It combines several approaches, including screening large numbers of natural products, chemical modification of known active molecules, identification of new drug targets, and rational design based on biological mechanisms and drug-receptor structure. These approaches are carried out in both academic research laboratories and...
7.9K
02:40Ligand Binding Sites
12.9K
Proteins are dynamic macromolecules that carry out a wide variety of essential processes; however, the activities of most proteins depend on their interactions with other molecules or ions, known as ligands.
Protein-ligand interactions are quite specific; even though numerous potential ligands surround a cellular protein at any given time, only a particular ligand can bind to that protein. Moreover, a ligand binds only to a dedicated area on the surface of the protein, known as the...
Protein-ligand interactions are quite specific; even though numerous potential ligands surround a cellular protein at any given time, only a particular ligand can bind to that protein. Moreover, a ligand binds only to a dedicated area on the surface of the protein, known as the...
12.9K
01:22Protein-Drug Binding: Determination Methods
201
Determining protein-drug binding can be achieved through indirect and direct methods, each providing valuable insights into the interaction between proteins and drugs.
Indirect methods involve isolating the bound drug from its free form in biological samples such as blood, serum, or plasma. These techniques aim to measure the percentage of drugs bound to proteins. Equilibrium dialysis is a commonly used method where the free drug concentration at equilibrium is measured by separating the bound...
Indirect methods involve isolating the bound drug from its free form in biological samples such as blood, serum, or plasma. These techniques aim to measure the percentage of drugs bound to proteins. Equilibrium dialysis is a commonly used method where the free drug concentration at equilibrium is measured by separating the bound...
201