On average, an approved drug today costs $2–3 billion and takes over ten years to develop 1 . In part, this is due to expensive and time-consuming wet-lab experiments, poor initial hit compounds, and the high attrition rates in the (pre-)clinical phases. Structure-based virtual screening (SBVS) has the potential to mitigate these problems. With SBVS, the quality of the hits improves with the number of compounds screened 2 . However, despite the fact that large compound databases exist, the ability to carry out large-scale SBVSs on computer clusters in an accessible, efficient, and flexible manner has remained elusive. Here we designed VirtualFlow, a highly automated and versatile open-source platform with perfect scaling behaviour that is able to prepare and efficiently screen ultra-large ligand libraries of compounds. VirtualFlow is able to use a variety of the most powerful docking programs. Using VirtualFlow, we have prepared the largest and freely available ready-to-dock ligand library available, with over 1.4 billion commercially available molecules. To demonstrate the power of VirtualFlow, we screened over 1 billion compounds and discovered a small molecule inhibitor (iKeap1) that engages KEAP1 with nanomolar affinity ( K d = 114 nM) and disrupts the interaction between KEAP1 and the transcription factor NRF2. We also identified a set of structurally diverse molecules that bind to KEAP1 with submicromolar affinity. This illustrates the potential of VirtualFlow to access vast regions of the chemical space and identify binders with high affinity for target proteins.
SARS-CoV-2 related proteins were targeted in ultra-large in silico screens. Multiple functional sites on individual target proteins were screened. 17 virus-related targets, 45 screens, and 50 billion docking instances were covered. Conservation in some target sites means hits could exhibit pancoronavirus function. Screening results are available as an interactive web resource and for download.
SARS-CoV-2 precipitates respiratory distress by infection of airway epithelial cells and is often accompanied by acute kidney injury. We report that Kidney Injury Molecule-1/T cell immunoglobulin mucin domain 1 (KIM-1/TIM-1) is expressed in lung and kidney epithelial cells in COVID-19 patients and is a receptor for SARS-CoV-2. Human and mouse lung and kidney epithelial cells express KIM-1 and endocytose nanoparticles displaying the SARS-CoV-2 spike protein (virosomes). Uptake was inhibited both by anti-KIM-1 antibodies and by TW-37, our newly discovered inhibitor of KIM-1-mediated endocytosis. Enhanced KIM-1 expression by human kidney tubuloids increased uptake of virosomes. KIM-1 positive cells express less angiotensin-converting enzyme 2 (ACE2), the well-known receptor for SARS-CoV-2. Using microscale thermophoresis, the EC50 for KIM-1-SARS-CoV-2 spike protein, and receptor binding domain (RBD) interactions, were 19 and 10 nM respectively. Thus KIM-1 is an alternative receptor to ACE2 for SARS-CoV-2. KIM-1 targeted therapeutics may prevent and/or treat COVID-19.
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