权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

RAPID: Identifying Biophysical Determinants of Binding to the SARS-CoV-2 Main Viral Protease

RAPID：识别与 SARS-CoV-2 主要病毒蛋白酶结合的生物物理决定因素

基本信息

批准号：
2033426
负责人：
John Chodera
金额：
$ 20万
依托单位：
Sloan Kettering Institute For Cancer Research
依托单位国家：
美国
项目类别：
Standard Grant
财政年份：
2020
资助国家：
美国
起止时间：
2020-07-01 至 2021-06-30
项目状态：
已结题

来源：
https://www.nsf.gov/awardsearch/showAward?AWD_ID=2033426&HistoricalAwards=false
关键词：
RAPID Identifying Biophysical Determinants Binding

项目摘要

John Chodera of the Sloan Kettering Institute for Cancer Research is supported by an award from the Chemical Theory, Models and Computational Methods program in the Division of Chemistry to identify the biophysical determinants of inhibition for the SARS-CoV-2 main viral protease (Mpro). Mpro is an essential enzyme in the virus that causes COVID-19. The Chodera lab develops physical models accelerated by inexpensive consumer-grade graphics processing units (GPUs) to predict which small molecules might bind and inhibit disease-relevant proteins. The Chodera lab is part of the Folding@home Consortium, a research collaboration that uses the Folding@home distributed computing environment to run these calculations. This computing resource is donated by a network of volunteers around the world. Recently, in response to the COVID-19 pandemic, Folding@home became the largest computing platform of any kind in the world, with 25M CPU cores and 600K GPUs participating at any given time. The Chodera lab will use Folding@home to integrate computation and experiment to rapidly identify high-affinity inhibitors of Mpro and to elucidate key interactions required for effective inhibition. They work with collaborators at Informatics Matters (a team that works to enumerates synthetically feasible compounds), Enamine (to synthesize compounds), the Diamond Light Source (to crystallize chemical compounds), the London lab at the Weizmann (to assay compounds), and PostEra (to make the results rapidly and publicly available in a manner that can accelerate research on Mpro inhibition in other research laboratories and pharmaceutical companies). Over the last two months, Folding@home has become the world’s largest computing resource (2.5 exaflops, 25M CPU cores, 600K GPUs) in service of COVID-19 specific research. John Chodera, a founding investigator in the Folding@home Consortium, and collaborators have established a rapid pipeline to go from the selection of molecules within the 14B compound Enamine REAL Space virtual synthetic library to key biophysical data (X-ray structures and affinities) to SARS-CoV-2 main viral protease (Mpro) with ~2 week turnaround time. His laboratory is now using relative alchemical free energy methods to assess strategies for rapidly progressing an initial set of 68 small molecule X-ray structures from an initial screen for weak inhibitors toward high-affinity ligands. The team also identifies key biophysical determinants of high-affinity ligand binding within the active site of Mpro, and benchmark the propsective accuracy of small molecule force fields to inform the development of next-generation force fields. The laboratory is selecting molecules from Enamine REAL Space to be synthesized, soaked to produce X-ray structures by DiamondMX/XChem, and assayed for Mpro inhibition by the London lab at the Weizmann Institute via collaborations already in place. All computational data is being rapidly disseminated online via the NSF-funded Molecular Sciences Software Institute (MolSSI) COVID-19 Molecular Structures and Therapeutics Hub and the open science COVID Moonshot program to maximize multiple downstream uses for fundamental research and the opportunity for broader impacts in applied and translational areas.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.

斯隆·凯特琳癌症研究所的John Chodera得到了化学部化学理论、模型和计算方法项目的支持，该奖项旨在确定SARS-CoV-2主要病毒蛋白水解酶(MPRO)抑制的生物物理决定因素。Mpro是导致新冠肺炎的病毒中的一种必不可少的酶。Chodera实验室开发了由廉价的消费级图形处理器(GPU)加速的物理模型，以预测哪些小分子可能结合和抑制与疾病相关的蛋白质。Chodera实验室是Folding@Home联盟的一部分，该联盟是一个研究合作机构，使用Folding@Home分布式计算环境来运行这些计算。这种计算资源是由世界各地的志愿者网络捐赠的。最近，为了应对新冠肺炎疫情，Folding@Home成为世界上最大的计算平台，在任何给定的时间都有2500万个CPU核心和60万个GPU参与。Chodera实验室将使用Folding@home整合计算和实验，以快速识别MPRO的高亲和力抑制剂，并阐明有效抑制所需的关键相互作用。他们与Informatics Matters(一个致力于列举合成可行化合物的团队)、Enamine(合成化合物)、钻石光源(结晶化合物)、伦敦魏兹曼实验室(分析化合物)和POSTA(以加速其他研究实验室和制药公司对MPRO抑制的研究)的合作者合作。在过去的两个月里，Folding@Home已经成为世界上最大的计算资源(250万次浮点运算，2500万个中央处理器核心，60万个GPU)，服务于新冠肺炎的特定研究。John Chodera是Folding@Home联合会的创始研究员之一，他和合作者已经建立了一条快速管道，从14B化合物Enamine Real Space虚拟合成文库中分子的选择到关键生物物理数据(X射线结构和亲和力)到SARS-CoV-2主要病毒蛋白酶(MPRO)，周转时间约为2周。他的实验室现在正在使用相对炼金术自由能方法来评估快速将最初的68个小分子X射线结构从最初的弱抑制剂筛选到高亲和力配体的策略。该团队还确定了MPRO活性部位内高亲和力配体结合的关键生物物理决定因素，并对小分子力场的预测精度进行了基准测试，以指导下一代力场的发展。该实验室正在从Enamine Real Space中选择要合成的分子，用DiamondMX/XChem浸泡以产生X射线结构，并通过已经到位的合作，由位于伦敦的魏兹曼研究所的实验室分析MPRO抑制。所有计算数据都通过美国国家科学基金会资助的分子科学软件研究所(MolSSI)新冠肺炎分子结构和治疗中心以及开放科学COVID登月计划在网上迅速传播，以最大限度地将基础研究的多个下游用途以及在应用和翻译领域产生更广泛影响的机会最大化。该奖项反映了美国国家科学基金会的法定使命，并通过使用基金会的智力优势和更广泛的影响审查标准进行评估，被认为值得支持。