Augmenting Hit Identification by Virtual Screening Techniques in Small Molecule Drug Discovery

Two
orthogonal approaches for hit identification in drug discovery
are large-scale in vitro and in silico screening. In recent years, due to the emergence of new targets
and a rapid increase in the size of the readily synthesizable chemical
space, there is a growing emphasis on the integration of the two techniques
to improve the hit finding efficiency. Here, we highlight three examples
of drug discovery projects at Merck & Co., Inc., Kenilworth, NJ,
USA in which different virtual screening (VS) techniques, each specifically
tailored to leverage knowledge available for the target, were utilized
to augment the selection of high-quality chemical matter for in vitro assays and to enhance the diversity and tractability
of hits. Central to success is a fully integrated workflow combining in silico and experimental expertise at every stage of the
hit identification process. We advocate that workflows encompassing
VS as part of an integrated hit finding plan should be widely adopted
to accelerate hit identification and foster cross-functional collaborations
in modern drug discovery.

在药物发现的命中物识别（hit identification）流程中，两大正交筛选策略分别为大规模体外实验（in vitro）筛选与计算机辅助（in silico）筛选。近年来，随着全新药物靶点的不断涌现，以及可快速合成的化学空间规模快速扩张，业界愈发重视将这两种技术进行整合，以提升命中物发现效率。本文聚焦美国新泽西州肯尼沃斯市默克公司（Merck & Co., Inc.）的三个药物发现项目案例，这些项目均采用了不同的虚拟筛选（virtual screening, VS）技术——每一种技术均针对对应靶点的已有知识进行定制化设计——用以辅助筛选高质量化学实体，用于后续体外实验测试，并提升命中物的多样性与可开发性。本研究的核心成功要素在于，在命中物识别流程的全阶段，构建了一套融合计算机辅助与实验研发专业能力的完整整合式工作流。我们主张，在现代药物发现领域，应广泛采用将虚拟筛选纳入整合式命中物发现方案的工作流，以加速命中物识别进程，并推动跨职能团队协作。