An Integrated Workflow Comprising AI, Physics and Experiment: Discovery of Nanomolar-Potent Inhibitors

The drug discovery process remains very slow and unreliable, requiring about 10 years and $2-3 billion for a single new drug at a success rate of around 5%. To address this, we have recently created a complex and highly heterogeneous workflow called IMPECCABLE which is designed to transform much of the drug discovery process into a far more reliable in silico environment. It runs on Frontier, the world’s first exascale machine and has recently been implemented on the second such machine, Aurora. A variety of in silico discovery methods exist, including physics-based and artificial intelligence (AI) approaches. Despite their limitations, these methods are complementary, and we combine them here within IMPECCABLE, an integrated framework which efficiently and reliably explores the vast chemical space of small molecule binders. IMPECCABLE involves screening, generating and evaluating candidate compounds. The environment is comprised of several interlocking and interacting stages. In the first of these, an exceptionally fast machine learning model acts as a docking surrogate for rapidly screening billions of compounds and provides a ranked series of binding poses for the best ones. In a generative multi-objective active learning loop, the accurate binding free energies from physics-based free energy methods, including ESMACS and TIES, guide REINVENT to predict compounds not only with higher binding affinities, but which are also synthesizable while ensuring diversity and novelty. The full iterative workflow spans both hit identification and hit-to-lead optimization and includes medicinal chemists in the process. Applying IMPECCABLE to two disease-related protein targets, WDR91 and TNKS2, we demonstrate its capability to iteratively produce experimentally makeable potent binders. The potential hits discovered were further optimized and chiral purified via an iterative REINVENT-TIES cycle. We identified a potent hit for WDR91, which was synthesised in five steps, exhibiting nanomolar binding affinity with a KD value of 352 ± 32 nM.