Evaluation of an In silico pipeline for drug discovery – a sustainable alternative model to laboratory based – drug discovery without borders.

药物发现是一个昂贵、耗时和不可持续的过程，需要庞大的团队、大量使用动物模型和大量的物理实验室资源。这一过程也容易失败，因为所使用的许多方法不能代表目标疾病状态或生物体。尽管在高通量筛选(THS)过程中投入了大量的生物、技术和财政资源，但落选率很高，甚至很少有竞争者进入人体试验。这一资源需求意味着，新冠肺炎大流行以及随后的实验室工作人员封锁对药物发现产生了重大影响。我们相信，使用基于计算机的人工智能驱动的方法可以替代这一过程，这里称为生物驱动的硅胶高通量筛选和药物发现。通过MDC，我们正在基于现有的人工智能硅胶(基于计算机的)工具构建药物发现管道。这些将在这个项目中用于确定肺癌中KRAS相关途径的替代药物靶点。这将通过将管道应用于公共储存库中持有的肺癌的高维分子数据(转录)来实现。我们的目标是确定一些可用药的竞争者和相关的小分子化合物，以此为靶点。我们还将通过快速自动细胞系验证来验证这些药物的生物学相关性。验证这一过程将提供一种替代的成本效益高的可持续药物发现方法，该方法可以在最少的资源限制下使用，减少对环境的影响，减少成本，减少动物的使用，并针对人类疾病。因此，我们将绕过当前HTS方法的许多限制。这将为新的具有成本效益的药物发现打开更多的机会，使药物能够在传统上缺乏投资的领域开发，例如罕见或孤儿疾病。

Drug discovery is an expensive, time consuming, and unsustainable process requiring large teams, significant use of animal models, and extensive physical laboratory resources. The process is also prone to failure because many of the methods used are unrepresentative of the disease state or organism being targetted. Despite the significant investment of biological, technical, and financial resources into the High Throughput Screening (THS) process, the drop off rate is high with few contenders even reaching trials in human subjects. This resource requirement has meant that drug discovery has been significantly impacted by the COVID-19 pandemic and subsequent lockdown of laboratory staff. We believe there is an alternative to this process using computer-based artificial intelligence-driven approaches here termed biologically driven In silico high throughput screening and drug discovery.With the MDC we are constructing a drug discovery pipeline based on existing artificial Intelligence in silico (computer-based) tools. These will be utilised in this project to identify alternative druggable targets for the KRas related pathway in lung cancer. This will be achieved through the application of the pipeline to high dimensional molecular data (transcriptomic) for lung cancer held in public repositories. We aim to identify a number of druggable contenders and associated small molecule-based compounds that can target these. We also will seek to validate the biological relevance of these through rapid automated cell line validation.The validation of this process will provide an alternative cost-effective sustainable approach to drug discovery which can be used with minimal resource constraints, reduced environmental impact, reduced costs, reduced use of animals, and human disease targetting. Thus we will circumvent many of the limitations of current HTS approaches. This will open up further opportunities for new cost-effective drug discovery allowing drugs to be developed in areas where there has traditionally been a lack of investment, such as rare or orphaned diseases.