The discovery of new drugs is a time consuming and expensive process. Methods such as virtual screening, which can filter out ineffective compounds from drug libraries prior to expensive experimental study, have become popular research topics. As the computational drug discovery community has grown, in order to benchmark the various advances in methodology, organizations such as the Drug Design Data Resource have begun hosting blinded grand challenges seeking to identify the best methods for ligand pose-prediction, ligand affinity ranking, and free energy calculations. Such open challenges offer a unique opportunity for researchers to partner with junior students (e.g., high school and undergraduate) to validate basic yet fundamental hypotheses considered to be uninteresting to domain experts. Here, we, a group of high school-aged students and their mentors, present the results of our participation in Grand Challenge 4 where we predicted ligand affinity rankings for the Cathepsin S protease, an important protein target for autoimmune diseases. To investigate the effect of incorporating receptor dynamics on ligand affinity rankings, we employed the Relaxed Complex Scheme, a molecular docking method paired with molecular dynamics-generated receptor conformations. We found that CatS is a difficult target for molecular docking and we explore some advanced methods such as distance-restrained docking to try to improve the correlation with experiments. This project has exemplified the capabilities of high school students when supported with a rigorous curriculum, and demonstrates the value of community-driven competitions for beginners in computational drug discovery.

中文翻译：

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将整体对接方法作为科学推广项目进行基准测试

新药的发现是一个耗时且昂贵的过程。虚拟筛选等方法可以在进行昂贵的实验研究之前从药物库中筛选出无效的化合物，已成为热门的研究主题。随着计算药物发现社区的发展，为了对方法学的各种进步进行基准测试，诸如药物设计数据资源之类的组织已开始承担蒙蔽的巨大挑战，以寻求确定用于配体姿势预测，配体亲和力排名和自由能计算。这样的开放性挑战为研究人员提供了与初中生（例如高中和大学本科生）合作以验证被领域专家不感兴趣的基本但基本假设的独特机会。在这里，我们，一群中学生和他们的导师介绍了我们参加“挑战4”的结果，我们在其中预测了组织蛋白酶S蛋白酶的配体亲和力排名，组织蛋白酶S蛋白酶是自身免疫性疾病的重要蛋白质靶标。为了研究结合受体动力学对配体亲和力等级的影响，我们采用了松弛复合方案，一种分子对接方法与分子动力学产生的受体构象配对。我们发现CatS是分子对接的困难目标，并且我们探索了一些先进的方法（例如距离约束对接）来尝试改善与实验的相关性。该项目通过严格的课程表彰了高中生的能力，