COVID-19 - Exploration of potential therapeutics against underexplored targets.

SARS CoV-2的基因组编码蛋白质，这些蛋白质执行病毒复制所必需的各种功能。通过利用我们对这些蛋白质的3D结构的了解，我们可以识别和/或设计与病毒蛋白质结合的小分子（即药物），以防止它们发挥正常功能。全球COVID-19研究小组一直在确定病毒基因组内编码的蛋白质的3D结构。研究的重点是Cov-2的主要靶蛋白，包括蛋白酶、刺突蛋白和解旋酶。也许令人惊讶的是，较少的努力是针对其他有希望的目标，有结构信息。我们专注于两个未充分研究的蛋白质，NSP 9（参与RNA加工）和E蛋白（一种病毒孔蛋白）。NSP 9帮助病毒复制其基因组。通过鉴定一种与NSP 9结合的化合物，我们将有一种潜在的药物来阻止感染细胞中的病毒复制。E蛋白是一种病毒孔蛋白，在受感染的细胞和病毒膜上形成通道。“堵塞”通道的分子（“通道阻断剂”）是潜在的抗病毒药物。对于靶蛋白，我们将把牛津大学的联合收割机先进分子模拟与IBM的人工智能驱动的潜在化合物鉴定相结合，以实现并加速鉴定可重新用作候选抗病毒药物的化合物。IBM生成式人工智能方法已经成功识别了新的抗菌药物，这些抗菌药物已得到实验验证。这里的工作将作为牛津大学和IBM之间长期合作的一部分进行，牢固的关系将确保这种高度合作的努力。

The genome of SARS CoV-2 encodes proteins which perform various functions essential for the replication of the virus. By exploiting our knowledge of the 3D structures of these proteins we can identify and/or design small molecules (i.e. drugs) that bind to viral proteins to prevent them from performing their normal function. COVID-19 research groups worldwide been determining 3D structures of proteins encoded within the viral genome. The focus has been on high-profile target proteins of Cov-2, including the protease, spike protein and helicases. Perhaps surprisingly, less effort is being directed towards other promising targets for which there is structural information. We focus on two underexplored proteins, NSP9 (involved in RNA processing) and E protein (a viroporin). NSP9 helps the virus to replicate its genome. By identifying a compound that binds to NSP9, we would have a potential drug to halt viral replication in infected cells. E protein is a viroporin, forming channels in infected cell and viral membranes. Molecules which 'plug' the channel ("channel blockers") are potential anti-viral drugs. For target proteins, we will combine advanced molecular simulations in Oxford with AI-driven identification of potential compounds by IBM to enable and accelerate identification of compounds which could be repurposed as candidate anti-viral drugs. The IBM generative AI method has already been successful in identifying new antimicrobials that have since been experimentally validated. The work here will be undertaken as part of a long-standing collaboration between Oxford and IBM and the strong relationship will ensure delivery of this highly collaborativeeffort.