快速有效地预测SARS-CoV-2主蛋白酶和20S蛋白酶的共价抑制剂的绝对结合自由能量
在PubMed上查看摘要
概括
此摘要是机器生成的。一种新的计算方法准确地预测了对共价抑制剂的结合能,这对于开发抗SARS-CoV-2主蛋白酶 (Mpro) 和其他点的药物至关重要.
科学领域
- 生物化学
- 计算化学
- 药物发现
背景情况
- COVID-19 流行需要新的治疗策略,共价抑制剂已成为针对 SARS-CoV-2 Mpro 等病毒蛋白酶的有希望的途径.
- 相对于传统药物,共价抑制剂具有优势,但准确预测它们的结合亲缘关系,特别是共价键形成,仍然是计算模型的挑战.
- 现有的计算方法难以捕捉共价键形成的复杂化学性质,阻碍了有效的抑制剂的设计.
研究的目的
- 开发和验证一个可靠的计算方法来预测共价抑制剂的绝对结合自由能量 (ABFE).
- 将量子力学与分子动力学结合起来, 准确地建模共价和非共价相互作用.
- 通过提供可靠的结合亲和力预测,加速新型共价抑制剂的设计.
主要方法
- 蛋白质二极管朗格温二极管 (PDLD/S-LRA/β) 方法与量子力学计算的整合.
- 在水性环境中计算抑制器弹头与目标氨基酸之间的反应能量.
- 应用该方法来预测针对SARS-CoV-2 Mpro和20S蛋白质组的共价抑制剂的ABFE.
主要成果
- 开发的计算方法可靠地预测共价抑制剂的ABFE,即使有不同的弹头.
- 该方法成功地捕获了共价相互作用和非共价相互作用的联合效应.
- 在SARS-CoV-2 Mpro和20S蛋白酶抑制剂中,获得了准确的ABFE预测.
结论
- 已经建立了一个强大的计算协议来预测共价抑制剂的绝对结合自由能量.
- 这种方法为合理设计有效的共价抑制剂提供了强大的工具,特别是针对SARS-CoV-2 Mpro.
- 该协议还可以帮助制定有针对性的蛋白质降解策略.
相关概念视频
Many proteins form complexes to carry out their functions, making protein-protein interactions (PPIs) essential for an organism's survival. Most PPIs are stabilized by numerous weak noncovalent chemical forces. The physical shape of the interfaces determines the way two proteins interact. Many globular proteins have closely-matching shapes on their surfaces, which form a large number of weak bonds. Additionally, many PPIs occur between two helices or between a surface cleft and a...
The equilibrium binding constant (Kb) quantifies the strength of a protein-ligand interaction. Kb can be calculated as follows when the reaction is at equilibrium:
where P and L are the unbound protein and ligand, respectively, and PL is the protein-ligand complex.
As the amount of bound ligand is also related to the rate of ligand binding, experiments can also determine Kb by examining the rates of protein-ligand association (kon) and dissociation (koff) using the following ratio:
Protein-drug binding refers to the interaction between drugs and proteins within the body. This binding process can occur intracellularly, involving drug interactions with enzymes or receptors within cells, or extracellularly, involving plasma proteins in the blood.
Various forces drive these interactions, including hydrogen bonds, hydrophobic interactions, ionic bonds, electrostatic interactions, and van der Waals forces. These bonds enable drugs to bind to specific sites on proteins,...
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...
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...
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...

