Lead optimization

潜在客户优化

• 批准号: 10513875
• 负责人: John Damon Chodera
• 金额: $ 2453.85万
• 依托单位: SLOAN-KETTERING INST CAN RESEARCH
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-05-16 至 2025-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10513875
• 关键词: Structure; lead optimization

In less than a year, the COVID Moonshot open science collaboration developed a novel non-peptidomimetic small molecule orally bioavailable SARS-CoV-2 main viral protease (Mpro) inhibitor with potent antiviral activity starting from a high-throughput fragment screen. To achieve this, rapid cycles of medicinal chemistry were performed, directed by a team composed of industry veterans with over 100 years of accumulated industry experience. The team leveraged Al-driven synthesis planning for rapidly sourcing molecules from CROs, high-throughput co-crystallisation data generated with just 1 week turnaround, and the world's largest computing network to perform hundreds of thousands of alchemical free energy calculations. About 2000 compounds were synthesized and assayed, and more than 450 X-ray structures solved in the process, generating rich structure-activity and property relationships for multiple lead series with distinct chemotypes. With a SARS-CoV-2 specific Mpro inhibitor now progressing to IND-enabling studies, the COVID Moonshot aims to harness the infrastructure it has built for pandemic preparedness. Our Lead Optimization proposal (Project 5) for the ASAP Center is to progress six early lead compounds developed by Project 3 and 4, towards readiness for preclinical development (Project 6). We anticipate that up to three preclinical packages will be developed within the Center, and three made available externally. Within Project 5, we will enhance and scale up existing lead optimization processes, building on the resources and collaborator network that rapidly produced and progressed the COVID Moonshot SARS-CoV-2 Mpro inhibitor en route to the clinic. Further, we will harness the knowledge and expertise of our new collaborators, lending cellular assays and antiviral models that are required to develop new direct acting antivirals for coronaviridae, flaviviridae and picornaviridae (Project 1 and antiviral core). In addition, we will develop our technology base: the co-location of integrated, tiered in vitro - in vivo ADMET screening cascades with our synthesis partners will increase efficiency, and exploiting cloud based material logistics and activity databases will optimize shipment and data logistics. We will work in a fully open-science model, to ensure resulting therapies can be produced at cost by manufacturers world-wide and secure long term availability for future pandemics whenever they arise. In addition to molecules that will be developed for pandemic preparedness and ultimate patient benefit, the integrated lead optimization datasets, with linked ADMET, protein-ligand structures underpinning designed compounds, synthesis routes, and antiviral assay, are anticipated to become a vital resource in the improvement of oral direct acting antiviral discovery as well as a foundational teaching resource.

在不到一年的时间里，COVID Moonshot开放科学合作开发出了一种新型非肽模拟物 具有强效抗病毒活性小分子口服生物可利用SARS-CoV-2主要病毒蛋白酶（Mpro）抑制剂 从高通量片段筛选开始。为了实现这一点，药物化学的快速循环， 由拥有100多年行业积累的行业资深人士组成的团队执导 体验.该团队利用Al驱动的合成计划快速从CRO采购分子， 高通量共结晶数据生成仅需1周的周转时间，是世界上最大的 计算网络来执行成千上万的炼金术自由能计算。约2000 化合物被合成和分析，在这个过程中解决了450多个X射线结构， 为具有不同化学型的多个铅系列产生丰富的结构-活性和性质关系。 随着SARS-CoV-2特异性Mpro抑制剂目前正在进行IND使能研究，COVID Moonshot 旨在利用其为大流行病准备而建立的基础设施。 我们为ASAP中心提出的先导化合物优化方案（项目5）是开发六种早期先导化合物 由项目3和4开发，为临床前开发做好准备（项目6）。我们预计， 到三个临床前包将在中心内开发，三个提供外部。内 项目5，我们将加强和扩大现有的铅优化流程，建立在资源和 合作者网络，迅速生产和发展COVID Moonshot SARS-CoV-2 Mpro抑制剂 在去诊所的路上此外，我们将利用新合作者的知识和专业知识， 开发新的直接作用于冠状病毒科的抗病毒药物所需的细胞测定和抗病毒模型， 黄病毒科和小核糖核酸病毒科（项目1和抗病毒核心）。此外，我们将发展我们的技术基础： 与我们的合成伙伴共同定位整合的、分层的体外-体内ADMET筛选级联， 提高效率，利用基于云的材料物流和活动数据库将优化运输 和数据物流。 我们将在一个完全开放的科学模式下工作，以确保最终的疗法可以以成本生产， 确保未来流行病发生时的长期可用性。在 除了为大流行准备和最终患者利益而开发的分子外， 集成的铅优化数据集，与关联的ADMET，蛋白质-配体结构支撑设计 化合物，合成路线和抗病毒测定，预计将成为一个重要的资源， 改善口服直接作用的抗病毒药物的发现以及基础教学资源。