ABSTRACT
We report the results of the COVID Moonshot, a fully open-science, crowdsourced, and structure-enabled drug discovery campaign targeting the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) main protease. We discovered a noncovalent, nonpeptidic inhibitor scaffold with lead-like properties that is differentiated from current main protease inhibitors. Our approach leveraged crowdsourcing, machine learning, exascale molecular simulations, and high-throughput structural biology and chemistry. We generated a detailed map of the structural plasticity of the SARS-CoV-2 main protease, extensive structure-activity relationships for multiple chemotypes, and a wealth of biochemical activity data. All compound designs (>18,000 designs), crystallographic data (>490 ligand-bound x-ray structures), assay data (>10,000 measurements), and synthesized molecules (>2400 compounds) for this campaign were shared rapidly and openly, creating a rich, open, and intellectual property-free knowledge base for future anticoronavirus drug discovery.
Subject(s)
COVID-19 Drug Treatment , Coronavirus 3C Proteases , Coronavirus Protease Inhibitors , Drug Discovery , SARS-CoV-2 , Humans , Coronavirus 3C Proteases/antagonists & inhibitors , Coronavirus 3C Proteases/chemistry , Molecular Docking Simulation , Coronavirus Protease Inhibitors/chemical synthesis , Coronavirus Protease Inhibitors/chemistry , Coronavirus Protease Inhibitors/pharmacology , Structure-Activity Relationship , Crystallography, X-RaySubject(s)
Antiviral Agents/analysis , COVID-19 Drug Treatment , Cooperative Behavior , Drug Discovery/methods , Drug Discovery/organization & administration , Drug Evaluation, Preclinical/methods , Open Access Publishing , Animals , Antiviral Agents/pharmacology , Antiviral Agents/therapeutic use , COVID-19/epidemiology , COVID-19/virology , Clinical Trials as Topic , Coronavirus 3C Proteases/antagonists & inhibitors , Coronavirus 3C Proteases/chemistry , Crowdsourcing , Crystallography, X-Ray/instrumentation , Drug Repositioning , Goals , Humans , International Cooperation , Israel/epidemiology , SARS-CoV-2/genetics , SARS-CoV-2/isolation & purification , Social Media , Synchrotrons , Time Factors , United Kingdom/epidemiology , Videoconferencing , Volunteers , World Health Organization/organization & administrationABSTRACT
The primary target of a novel series of immunosuppressive 7-piperazin-1-ylthiazolo[5,4- d]pyrimidin-5-amines was identified as the lipid kinase, PI4KIIIß. Evaluation of the series highlighted their poor solubility and unwanted off-target activities. A medicinal chemistry strategy was put in place to optimize physicochemical properties within the series, while maintaining potency and improving selectivity over other lipid kinases. Compound 22 was initially identified and profiled in vivo, before further modifications led to the discovery of 44 (UCB9608), a vastly more soluble, selective compound with improved metabolic stability and excellent pharmacokinetic profile. A co-crystal structure of 44 with PI4KIIIß was solved, confirming the binding mode of this class of inhibitor. The much-improved in vivo profile of 44 positions it as an ideal tool compound to further establish the link between PI4KIIIß inhibition and prolonged allogeneic organ engraftment, and suppression of immune responses in vivo.
Subject(s)
Enzyme Inhibitors/pharmacology , Enzyme Inhibitors/pharmacokinetics , Phosphotransferases (Alcohol Group Acceptor)/antagonists & inhibitors , Piperazines/pharmacology , Piperazines/pharmacokinetics , Piperidines/pharmacology , Transplantation, Homologous , Administration, Oral , Animals , Biological Availability , Enzyme Inhibitors/administration & dosage , Enzyme Inhibitors/metabolism , Humans , Immunosuppressive Agents/administration & dosage , Immunosuppressive Agents/metabolism , Immunosuppressive Agents/pharmacokinetics , Immunosuppressive Agents/pharmacology , Mice , Molecular Docking Simulation , Phosphotransferases (Alcohol Group Acceptor)/chemistry , Phosphotransferases (Alcohol Group Acceptor)/metabolism , Piperazines/administration & dosage , Piperazines/metabolism , Piperidines/administration & dosage , Piperidines/metabolism , Protein ConformationABSTRACT
Double electron-electron resonance in conjunction with site-directed spin labeling has been used to probe natural conformational sampling of the human tumor necrosis factor α trimer. We suggest a previously unreported, predeoligomerization conformation of the trimer that has been shown to be sampled at low frequency. A model of this trimeric state has been constructed based on crystal structures using the double-electron-electron-resonance distances. The model shows one of the protomers to be rotated and tilted outward at the tip end, leading to a breaking of the trimerous symmetry and distortion at a receptor-binding interface. The new structure offers opportunities to modulate the biological activity of tumor necrosis factor α through stabilization of the distorted trimer with small molecules.
Subject(s)
Electron Spin Resonance Spectroscopy , Tumor Necrosis Factor-alpha/metabolism , Escherichia coli , Humans , Models, Molecular , Mutation , Protein Multimerization , Protein Stability , Protein Structure, Quaternary , Spin Labels , Tumor Necrosis Factor-alpha/chemistry , Tumor Necrosis Factor-alpha/geneticsABSTRACT
Computational searches for novel ligands for a given protein binding site have become ubiquitous in the pharmaceutical industry, and are potentially equally useful in helping identify small-molecule tools for biology. Here we describe the steps needed to carry out a high-throughput docking (HTD) or three-dimensional (3D) pharmacophore virtual screen starting with a model of the target protein's structure. The advice given is, in most cases, software independent but some tips are provided which apply only to certain popular programs. Useful work can be carried out using free programs on a modest workstation. Of course, any resultant "hits" remain in the virtual world until they are experimentally tested.
Subject(s)
Molecular Docking Simulation , Proteins/chemistry , Small Molecule Libraries/chemistry , Software , Binding Sites , Drug Discovery , High-Throughput Screening Assays , Humans , Hydrogen Bonding , Ligands , Molecular Conformation , Protein Binding , Static Electricity , ThermodynamicsABSTRACT
A series of 4-azaindole inhibitors of c-Met kinase is described. The postulated binding mode was confirmed by an X-ray crystal structure and series optimisation was performed on the basis of this structure. Future directions for series development are discussed.
Subject(s)
Indoles/chemistry , Protein Kinase Inhibitors/chemistry , Proto-Oncogene Proteins c-met/antagonists & inhibitors , Cell Line, Tumor , Computer Simulation , Crystallography, X-Ray , Drug Discovery , Humans , Indoles/chemical synthesis , Indoles/pharmacology , Protein Kinase Inhibitors/chemical synthesis , Protein Kinase Inhibitors/pharmacology , Proto-Oncogene Proteins c-met/metabolism , Structure-Activity RelationshipABSTRACT
A series of quinoxaline inhibitors of c-Met kinase is described. The postulated binding mode was confirmed by an X-ray crystal structure and optimisation of the series was performed on the basis of this structure. Future directions for development of the series are discussed together with the identification of a novel quinoline scaffold.
