DMREF: Accelerated discovery of metastable but persistent contact insecticide crystal polymorphs for enhanced activity and sustainability

DMREF：加速发现亚稳态但持久的接触性杀虫剂晶体多晶型物，以增强活性和可持续性

• 批准号: 2118890
• 负责人: Mark Tuckerman
• 金额: $ 171.36万
• 依托单位: New York University
• 依托单位国家: 美国
• 项目类别: Standard Grant
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-04-01 至 2026-03-31
• 项目状态: 未结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=2118890&HistoricalAwards=false
• 关键词: DMREF; Accelerated; discovery; metastable; but

Non-technical Description: The World Health Organization estimates that malaria and other vector-borne infectious diseases, such as Zika or dengue fever, are responsible for more than 700,000 deaths worldwide annually. An essential component in the fight against malaria is the control of disease vectors through the use of contact insecticides for indoor residual spraying and insecticide-treated nets. Contact insecticides are powders of organic crystalline materials. As mosquitoes rest on the powder particles, they absorb the active substance through their tarsi (feet) to lethal effect. New York University investigators previously demonstrated that the efficacy of contact insecticides strongly depends on the identity of their crystalline forms, otherwise known as polymorphs, which have identical molecular compositions but different crystal structures. The more active polymorphs must also exhibit a high stability against transformation to less active polymorphs for the duration of their application. The central objective of this project is a knowledge-guided design, through computation and experiment, of metastable crystalline forms with superior properties for their target application. In the context of contact insecticides, this will allow less toxicant to be used, reduce environmental impact, and, thereby, meet key sustainability goals on multiple fronts. Various workshops, including Computer Crystals for Kids, Machine Learning for Kids, and Crystal Kaleidoscope, will convey the science of the project to K-12 students. Special attention will be provided to engage Black, Latino, and Native American students through the Collegiate Science Technology Entry Program.Technical Description: The application of metastable polymorphs of molecular crystals in the management of vector-borne diseases such as malaria and dengue fever through innovations in contact insecticide formulations represents a new and sustainable target of opportunity. Accelerated discovery of such metastable polymorphs with low thermodynamic yet high kinetic stability constitutes a key challenge that can only be met using a tightly integrated computational and experimental workflow. Starting with twelve known contact insecticides approved by the World Health Organization for indoor residual spraying (including pyrethroids, organophosphates, carbamates, and neonicotinoids), the project will explore innovative approaches to crystal polymorphs that meet the aforementioned criteria, which are essential to insecticide efficacy that relies on physical contact between insect tarsi and crystal surfaces in indoor residual spraying applications and insecticide-treated nets. Experimentally, these metastable polymorphs can be obtained from melt or solution, by (cross-)nucleation, phase transformations, or growth under nanoconfinement. The experimental work will be complemented by the development of a theoretical framework focused on the formation of energetically accessible polymorphs – driven by both thermodynamic and kinetic factors – as well as the transformation between different polymorphs and their surface properties. These tasks are beyond the reach of standard computational tools, requiring the development of new theoretical methodologies that combine the strength of enhanced molecular simulations and machine learning. Initial computational results will be validated by experimental data to improve the theoretical framework. Similarly, theoretical predictions will be used to guide and refine experimental protocols. This iterative loop of mutual feedback will eventually converge toward comprehensive and reliable workflows that will accelerate the discovery and development of metastable polymorphs with exceptional properties, in accord with the goals of the Materials Genome Initiative. Various workshops, including Computer Crystals for Kids, Machine Learning for Kids, and Crystal Kaleidoscope, will convey the science of the project to K-12 students. Special attention will be provided to engage Black, Latino, and Native American students through the Collegiate Science Technology Entry Program.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.

非技术性描述：世界卫生组织估计，疟疾和其他媒介传播的传染病（例如寨卡病毒或登革热）导致全世界超过 70 万人死亡，控制疾病是抗击疟疾的一个重要组成部分。通过使用室内滞留喷洒的接触性杀虫剂和经杀虫剂处理的蚊帐传播媒介。接触性杀虫剂是有机结晶材料的粉末，当蚊子停留在粉末颗粒上时，它们通过其吸收活性物质。纽约大学的研究人员此前证明，接触性杀虫剂的功效很大程度上取决于其晶型的特性，也称为多晶型物，它们具有相同的分子组成，但晶体结构不同。该项目的中心目标是通过计算和实验，在其目标应用中具有优异性能的亚稳态晶型的知识引导设计。语境接触性杀虫剂的使用，这将减少有毒物质的使用，减少对环境的影响，从而实现多个方面的关键可持续发展目标，包括儿童计算机水晶、儿童机器学习和水晶万花筒等各种研讨会将传达这一理念。将特别关注通过大学科学技术入门计划吸引黑人、拉丁裔和美国原住民学生的项目科学。技术描述：分子晶体亚稳态多晶型物在管理中的应用通过接触性杀虫剂配方的创新来治疗疟疾和登革热等媒介传播疾病代表了一个新的、可持续的机会目标，加速发现这种具有低热力学但高动力学稳定性的亚稳态多晶型物构成了一个关键挑战，只能通过紧密的合作来应对。该项目将从世界卫生组织批准用于室内滞留喷洒的十二种已知接触性杀虫剂（包括拟除虫菊酯、有机磷酸酯、氨基甲酸酯和新烟碱类杀虫剂）开始。探索满足上述标准的晶体多晶型物的创新方法，这对于杀虫剂功效至关重要，其依赖于室内滞留喷洒应用和经杀虫剂处理的蚊帐中昆虫跗节和晶体表面之间的物理接触。实验上，这些亚稳态多晶型物可以从熔化中获得。或解决方案，通过（交叉）成核、相变或纳米限制下的生长，实验工作将得到一个理论框架的发展，该框架专注于由热力学和驱动力驱动的能量可接近的多晶型物的形成。动力学因素以及不同多晶型物及其表面特性之间的转换，这些任务超出了标准计算工具的能力范围，需要开发结合增强分子模拟和机器学习的力量的新理论方法。同样，理论预测将用于指导和完善实验方案，这种相互反馈的迭代循环最终将趋向于全面可靠的工作流程，从而加速亚稳态多晶型物的发现和开发。根据材料基因组计划的目标，各种研讨会（包括儿童计算机水晶、儿童机器学习和水晶万花筒）将向 K-12 学生传达该项目的科学知识。通过大学科学技术入门计划吸引黑人、拉丁裔和美国原住民学生。该奖项反映了 NSF 的法定使命，并通过使用基金会的智力优点和更广泛的影响审查标准进行评估，被认为值得支持。

项目成果

ROY Crystallization on Poly(ethylene) Fibers, a Model for Bed Net Crystallography

聚乙烯纤维上的 ROY 结晶，床网晶体学模型

• DOI: 10.1021/acs.chemmater.3c03188
• 发表时间: 2024-02
• 期刊: Chemistry of Materials
• 影响因子: 8.6
• 作者: Erriah, Bryan;Shtukenberg, Alexander G.;Aronin, Reese;McCarthy, Derik;Brázda, Petr;Ward, Michael D.;Kahr, Bart
• 通讯作者: Kahr, Bart

Efficient Polymorph Screening through Crystallization from Bulk and Confined Melts

通过块状和密闭熔体的结晶进行有效的多晶型筛选

• DOI: 10.1021/acs.cgd.2c01065
• 发表时间: 2022-12
• 期刊: Crystal Growth & Design
• 影响因子: 3.8
• 作者: Fellah, Noalle;Tahsin, Lamia;Zhang, Carolyn Jin;Kahr, Bart;Ward, Michael D.;Shtukenberg, Alexander G.
• 通讯作者: Shtukenberg, Alexander G.

Geometric Deep Learning for Molecular Crystal Structure Prediction

用于分子晶体结构预测的几何深度学习

• DOI: 10.1021/acs.jctc.3c00031
• 发表时间: 2023-07-25
• 期刊: Journal of Chemical Theory and Computation
• 影响因子: 5.5
• 作者: Kilgour, Michael;Rogal, Jutta;Tuckerman, Mark
• 通讯作者: Tuckerman, Mark