Global Discovery Chemistry, Novartis Institute for Biomedical Research, Novartis Pharma AG, Novartis Campus, 4056, Basel, Switzerland.
Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, Universitetsparken 2, 2100, Copenhagen, Denmark.
ChemMedChem. 2023 May 2;18(9):e202300002. doi: 10.1002/cmdc.202300002. Epub 2023 Mar 9.
Hit generation is a crucial step in drug discovery that will determine the speed and chance of success of identifying drug candidates. Many strategies are now available to identify chemical starting points, or hits, and each biological target warrants a tailored approach. In this set of best practices, we detail the essential approaches for target centric hit generation and the opportunities and challenges they come with. We then provide guidance on how to validate hits to ensure medicinal chemistry is only performed on compounds and scaffolds that engage the target of interest and have the desired mode of action. Finally, we discuss the design of integrated hit generation strategies that combine several approaches to maximize the chance of identifying high quality starting points to ensure a successful drug discovery campaign.
苗头化合物的发现是药物研发过程中的关键步骤，它决定了候选药物的鉴定速度和成功率。目前有许多策略可用于确定化学起始点，即苗头化合物，而且每个生物靶点都需要量身定制的方法。在这组最佳实践中，我们详细介绍了基于靶点的苗头化合物发现的基本方法，以及它们所带来的机遇和挑战。然后，我们提供了关于如何验证苗头化合物的指导，以确保仅对与目标靶点结合并具有预期作用模式的化合物和支架进行药物化学研究。最后，我们讨论了集成苗头化合物发现策略的设计，该策略结合了几种方法，以最大限度地提高鉴定高质量起始点的机会，从而确保药物研发项目的成功。
