Molecular Dynamics Simulations and Binding Free Energy Calculations to Discover New Insights into NLRP3 Inhibitors

IF 1.2 4区医学 Q4 CHEMISTRY, MEDICINAL

Letters in Drug Design & Discovery Pub Date : 2024-07-02 DOI:10.2174/0115701808303890240620074039

Karla Joane da Silva Menezes, Fernanda De França Genuíno Ramos Campos, Marianny de Souza, Daniel Calazans Medeiros, Igor José dos Santos Nascimento, Ricardo Olimpio de Moura

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引用次数: 0

Abstract

Background: Inflammation is an immunological reaction against an aggressor agent. NLRP3 inflammasome is a component of the immune system, which, when excessively activated, results in several inflammatory diseases, making it an attractive target for discovering antiinflammatory drugs. Computer-Aided Drug Design (CADD) techniques are powerful tools used to search for new drugs in less time and financial cost. Recently, studies demonstrated the CADD methods to discover information about NLRP3 inhibitors MCC950 and NP3-146. In addition, the discovery of GDC-2394 and its evaluation in clinical trials instigate new studies to find binding modes and structural attributes that can used in drug design works against this target. Objectives: Here, molecular modeling methods were used to discover the significant interactions of GDC-2394, MCC950, and NP3-146 with NLRP3 to obtain helpful information in drug design compared to other inhibitors. Methods: Molecular docking was performed using GOLD software. The best complexes were submitted into molecular dynamics simulations using GROMACS software, and the MM-PBSA was used to provide the free binding energy, which was performed using the tool g_mmpbsa compiled in GROMACS. Results: The RMSD, RMSF, Rg, SASA, and H-bond plots showed that the compound was stable during MD simulation time (100 ns) for GDC-2394. The PCA analysis for all compounds verified similar variance of the complex with the inhibitors to the apo-NLRP3, indicative of stability. DCCM analysis showed the best correlation in residues 134 - 371 region, which contains critical amino acids from the binding site (Ala227, Ala228, and Arg578), besides the newly identified residues. Using MMPBSA to provide the binding free energy, it was observed that the high affinity of the drugs against NLRP3 is related to the lower rigidity of the structure. Furthermore, we identified the critical residues Phe575, Pro352, Tyr632, and Met661 related to the coupling process. result: Then, RMSD, RMSF, Rg, SASA, and H-bond plots showed that the compound was stable during MD simulation time (100 ns) for GDC-2394. The PCA analysis for all compounds verified similar variance of the complex with the inhibitors to the apo-NLRP3, indicative of stability. Through DCCM analysis, the best correlation was observed in residues 134 - 371 region, which contains critical amino acids from the binding site (Ala227, Ala228, and Arg578), besides the newly identified residues. Using MM-PBSA to provide the binding free energy, it was observed that the high affinity of the drugs against NLRP3 is related to the lower rigidity of the structure. Furthermore, we identified the critical residues Phe575, Pro352, Tyr632, and Met661 related to the coupling process. Conclusion: Thus, these discoveries may contribute to the development of new anti-inflammatory drugs, such as NLRP3 inhibitors.

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通过分子动力学模拟和结合自由能计算发现 NLRP3 抑制剂的新见解

背景：炎症是一种针对侵略者的免疫反应。NLRP3 炎症小体是免疫系统的一个组成部分，一旦过度激活，就会导致多种炎症性疾病，因此是发现抗炎药物的一个有吸引力的靶点。计算机辅助药物设计（CADD）技术是一种强大的工具，可用于在更短的时间内、以更低的成本寻找新药。最近的研究表明，CADD方法可以发现NLRP3抑制剂MCC950和NP3-146的信息。此外，GDC-2394 的发现及其在临床试验中的评估促进了新的研究，以寻找可用于针对该靶点的药物设计工作的结合模式和结构属性。研究目的：本文采用分子建模方法发现 GDC-2394、MCC950 和 NP3-146 与 NLRP3 的重要相互作用，以获得与其他抑制剂相比对药物设计有帮助的信息。方法：使用 GOLD 软件进行分子对接。使用 GROMACS 软件对最佳复合物进行分子动力学模拟，并使用 GROMACS 中编译的工具 g_mmpbsa 利用 MM-PBSA 提供自由结合能。结果：RMSD、RMSF、Rg、SASA 和 H 键图显示，GDC-2394 的化合物在 MD 模拟时间（100 ns）内是稳定的。对所有化合物进行的 PCA 分析表明，与抑制剂形成的复合物与 apo-NLRP3 复合物的方差相似，表明其具有稳定性。DCCM 分析表明残基 134 - 371 区域的相关性最好，该区域除了新发现的残基外，还包含结合位点的关键氨基酸（Ala227、Ala228 和 Arg578）。利用 MMPBSA 提供的结合自由能观察到，药物对 NLRP3 的高亲和力与结构的低刚性有关。此外，我们还确定了与耦合过程有关的关键残基 Phe575、Pro352、Tyr632 和 Met661：然后，RMSD、RMSF、Rg、SASA 和 H 键图显示，GDC-2394 的化合物在 MD 模拟时间（100 ns）内是稳定的。对所有化合物进行的 PCA 分析验证了抑制剂与 apo-NLRP3 复合物的相似方差，这表明了稳定性。通过 DCCM 分析，在残基 134 - 371 区域观察到了最佳相关性，该区域除了新发现的残基外，还包含结合位点的关键氨基酸（Ala227、Ala228 和 Arg578）。利用 MM-PBSA 提供的结合自由能观察到，药物对 NLRP3 的高亲和力与结构的低刚性有关。此外，我们还发现了与耦合过程有关的关键残基 Phe575、Pro352、Tyr632 和 Met661。结论：因此，这些发现可能有助于开发新的抗炎药物，如 NLRP3 抑制剂。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Letters in Drug Design & Discovery 医学-医药化学

CiteScore

1.80

自引率

10.00%

发文量

245

审稿时长

3 months

期刊介绍： Aims & Scope Letters in Drug Design & Discovery publishes letters, mini-reviews, highlights and guest edited thematic issues in all areas of rational drug design and discovery including medicinal chemistry, in-silico drug design, combinatorial chemistry, high-throughput screening, drug targets, and structure-activity relationships. The emphasis is on publishing quality papers very rapidly by taking full advantage of latest Internet technology for both submission and review of manuscripts. The online journal is an essential reading to all pharmaceutical scientists involved in research in drug design and discovery.