Discovery Chemistry, Genentech, South San Francisco, USA.
Proteros Biostructures GmbH, Planegg, Germany.
Nat Commun. 2022 Oct 28;13(1):6447. doi: 10.1038/s41467-022-33981-8.
With the ever-increasing number of synthesis-on-demand compounds for drug lead discovery, there is a great need for efficient search technologies. We present the successful application of a virtual screening method that combines two advances: (1) it avoids full library enumeration (2) products are evaluated by molecular docking, leveraging protein structural information. Crucially, these advances enable a structure-based technique that can efficiently explore libraries with billions of molecules and beyond. We apply this method to identify inhibitors of ROCK1 from almost one billion commercially available compounds. Out of 69 purchased compounds, 27 (39%) have K values < 10 µM. X-ray structures of two leads confirm their docked poses. This approach to docking scales roughly with the number of reagents that span a chemical space and is therefore multiple orders of magnitude faster than traditional docking.
随着用于药物先导发现的按需合成化合物数量的不断增加，对高效搜索技术的需求也越来越大。我们展示了一种虚拟筛选方法的成功应用，该方法结合了两项进展：（1）它避免了对整个文库的枚举，（2）通过分子对接评估产物，利用蛋白质结构信息。至关重要的是，这些进展使基于结构的技术能够有效地探索数十亿乃至更多分子的文库。我们将该方法应用于从近十亿种商业上可获得的化合物中鉴定 ROCK1 的抑制剂。在购买的 69 种化合物中，有 27 种（39%）的 K 值<10µM。两种先导化合物的 X 射线结构证实了它们对接的构象。这种对接方法与跨越化学空间的试剂数量大致成比例，因此比传统的对接方法快几个数量级。
