Boss Christoph, Hazemann Julien, Kimmerlin Thierry, von Korff Modest, Lüthi Urs, Peter Oliver, Sander Thomas, Siegrist Romain
Drug Discovery & Preclinical Development Idorsia Pharmaceuticals Ltd Hegenheimermattweg 91, CH-4123 Allschwil;, Email:
Drug Discovery & Preclinical Development Idorsia Pharmaceuticals Ltd Hegenheimermattweg 91, CH-4123 Allschwil.
Chimia (Aarau). 2017 Oct 25;71(10):667-677. doi: 10.2533/chimia.2017.667.
In this case study on an essential instrument of modern drug discovery, we summarize our successful efforts in the last four years toward enhancing the Actelion screening compound collection. A key organizational step was the establishment of the Compound Library Committee (CLC) in September 2013. This cross-functional team consisting of computational scientists, medicinal chemists and a biologist was endowed with a significant annual budget for regular new compound purchases. Based on an initial library analysis performed in 2013, the CLC developed a New Library Strategy. The established continuous library turn-over mode, and the screening library size of 300'000 compounds were maintained, while the structural library quality was increased. This was achieved by shifting the selection criteria from 'druglike' to 'leadlike' structures, enriching for non-flat structures, aiming for compound novelty, and increasing the ratio of higher cost 'Premium Compounds'. Novel chemical space was gained by adding natural compounds, macrocycles, designed and focused libraries to the collection, and through mutual exchanges of proprietary compounds with agrochemical companies. A comparative analysis in 2016 provided evidence for the positive impact of these measures. Screening the improved library has provided several highly promising hits, including a macrocyclic compound, that are currently followed up in different Hit-to-Lead and Lead Optimization programs. It is important to state that the goal of the CLC was not to achieve higher HTS hit rates, but to increase the chances of identified hits to serve as the basis of successful early drug discovery programs. The experience gathered so far legitimates the New Library Strategy.
在这个关于现代药物发现关键工具的案例研究中，我们总结了过去四年里为扩充Actelion筛选化合物库所做的成功努力。一个关键的组织举措是在2013年9月成立了化合物库委员会（CLC）。这个由计算科学家、药物化学家以及一名生物学家组成的跨职能团队被赋予了可观的年度预算，用于定期采购新化合物。基于2013年进行的初始库分析，CLC制定了新的库策略。既定的连续库更新模式得以维持，筛选库规模保持在30万种化合物，同时结构库质量得到提升。这是通过将选择标准从“类药”结构转变为“类先导”结构、富集非平面结构、追求化合物新颖性以及提高高成本“优质化合物”的比例来实现的。通过向化合物库中添加天然化合物、大环化合物、设计库和聚焦库，以及与农用化学品公司相互交换专利化合物，获得了新的化学空间。2016年的一项对比分析证明了这些措施的积极影响。对改进后的库进行筛选已经获得了几个非常有前景的命中化合物，包括一种大环化合物，目前正在不同的从命中化合物到先导化合物以及先导化合物优化项目中跟进。需要指出的是，CLC的目标不是实现更高的高通量筛选命中率，而是增加所鉴定命中化合物成为成功早期药物发现项目基础的机会。迄今为止积累的经验证明了新库策略的合理性。
