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使用 ffTK 对带有卤素 σ-hole 粒子的药物分子进行参数化:实现、测试和比较。

Parameterization of a drug molecule with a halogen σ-hole particle using ffTK: Implementation, testing, and comparison.

机构信息

School of Physics, Georgia Institute of Technology, Atlanta, Georgia 30332, USA.

NIH Center for Macromolecular Modeling and Bioinformatics, Beckman Institute for Advanced Science and Technology, Department of Biochemistry, and Center for Biophysics and Quantitative Biology, University of Illinois at Urbana-Champaign, Urbana, Illinois 61801, USA.

出版信息

J Chem Phys. 2020 Oct 28;153(16):164104. doi: 10.1063/5.0022802.


DOI:10.1063/5.0022802
PMID:33138412
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC10198747/
Abstract

Halogen atoms are widely used in drug molecules to improve their binding affinity for the receptor proteins. Many of the examples involve "halogen bonding" between the molecule and the binding site, which is a directional interaction between a halogen atom and a nucleophilic atom. Such an interaction is induced by an electron cloud shift of the halogen atom toward its covalently bonded neighbor to form the σ-bond, leaving a small electrostatic positive region opposite to the bond called the "σ-hole." To mimic the effect of the σ-hole in the CHARMM non-polarizable force field, recently CGenFF added a positively charged massless particle to halogen atoms, positioned at the opposite side of the carbon-halogen bond. This particle is referred to as a lone pair (LP) particle because it uses the lone pair implementation in the CHARMM force field. Here, we have added support for LP particles to ffTK, an automated force field parameterization toolkit widely distributed as a plugin to the molecular visualization software VMD. We demonstrate the updated optimization process using an example halogenated drug molecule, AT130, which is a capsid assembly modulator targeting the hepatitis B virus. Our results indicate that parameterization with the LP particle significantly improves the accuracy of the electrostatic response of the molecule, especially around the halogen atom. Although the inclusion of the LP particle does not produce a prominent effect on the interactions between the molecule and its target protein, the protein-ligand binding performance is greatly improved by optimization of the parameters.

摘要

卤素原子广泛用于药物分子中,以提高它们与受体蛋白的结合亲和力。许多例子涉及分子和结合位点之间的“卤素键合”,这是卤素原子和亲核原子之间的一种定向相互作用。这种相互作用是由卤素原子的电子云向其共价键邻原子的移动引起的,形成σ键,在键的相反侧留下一个小的静电正区域,称为“σ空穴”。为了模拟 CHARMM 非极化力场中σ空穴的效果,最近 CGenFF 在卤素原子上添加了一个带正电的无质量粒子,位于碳-卤键的对面。这个粒子被称为孤对(LP)粒子,因为它使用 CHARMM 力场中的孤对实现。在这里,我们在 ffTK 中添加了对 LP 粒子的支持,ffTK 是一个自动化的力场参数化工具包,作为分子可视化软件 VMD 的插件广泛分发。我们使用一个示例卤化药物分子 AT130 演示了更新的优化过程,该分子是一种针对乙型肝炎病毒的衣壳组装调节剂。我们的结果表明,使用 LP 粒子参数化可以显著提高分子的静电响应的准确性,特别是在卤素原子周围。尽管包含 LP 粒子不会对分子与其靶蛋白之间的相互作用产生显著影响,但通过参数优化大大提高了蛋白-配体结合性能。

相似文献

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Parameterization of a drug molecule with a halogen σ-hole particle using ffTK: Implementation, testing, and comparison.

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引用本文的文献

[1]
Machine Learning of Molecular Dynamics Simulations Provides Insights into the Modulation of Viral Capsid Assembly.

J Chem Inf Model. 2025-5-26

[2]
Weighted Ensemble Simulations Reveal Novel Conformations and Modulator Effects in Hepatitis B Virus Capsid Assembly.

bioRxiv. 2025-3-17

[3]
Broadening access to small-molecule parameterization with the force field toolkit.

J Chem Phys. 2024-6-28

[4]
VMD as a Platform for Interactive Small Molecule Preparation and Visualization in Quantum and Classical Simulations.

J Chem Inf Model. 2023-8-14

[5]
Diclofenac and other non-steroidal anti-inflammatory drugs (NSAIDs) are competitive antagonists of the human P2X3 receptor.

Front Pharmacol. 2023-3-16

[6]
On the force field optimisation of [Formula: see text]-lactam cores using the force field Toolkit.

J Comput Aided Mol Des. 2022-7

[7]
All-Atom MD Simulations of the HBV Capsid Complexed with AT130 Reveal Secondary and Tertiary Structural Changes and Mechanisms of Allostery.

Viruses. 2021-3-26

本文引用的文献

[1]
Scalable molecular dynamics on CPU and GPU architectures with NAMD.

J Chem Phys. 2020-7-28

[2]
Serotonin transporter-ibogaine complexes illuminate mechanisms of inhibition and transport.

Nature. 2019-4-24

[3]
Treatment of Chronic Hepatitis B Virus Infection Using Small Molecule Modulators of Nucleocapsid Assembly: Recent Advances and Perspectives.

ACS Infect Dis. 2019-5-10

[4]
Improved Modeling of Halogenated Ligand-Protein Interactions Using the Drude Polarizable and CHARMM Additive Empirical Force Fields.

J Chem Inf Model. 2018-11-27

[5]
Structural and dynamic basis of substrate permissiveness in hydroxycinnamoyltransferase (HCT).

PLoS Comput Biol. 2018-10-26

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Structural basis of neurosteroid anesthetic action on GABA receptors.

Nat Commun. 2018-9-28

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Do Halogen-Hydrogen Bond Donor Interactions Dominate the Favorable Contribution of Halogens to Ligand-Protein Binding?

J Phys Chem B. 2017-7-11

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Heteroaryldihydropyrimidine (HAP) and Sulfamoylbenzamide (SBA) Inhibit Hepatitis B Virus Replication by Different Molecular Mechanisms.

Sci Rep. 2017-2-13

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Nat Methods. 2017-1

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