The Structural Genomics Consortium (SGC) is a public-private-partnership focusing on elucidating the functions and disease relevance of all proteins encoded by the human genome, with an emphasis on those that are relatively understudied. [1] [2] [3] The SGC places all its research output into the public domain without restriction and does not file for patents and continues to promote open science. [4] [5] [6] [7] [8] [9] [10] [11] [12] [13] [14] Two recent publications revisit the case for open science. [15] [16] Founded in 2003, and modelled after the Single Nucleotide Polymorphism Database (dbSNP) Consortium, the SGC is a charitable company whose Members comprise organizations that contribute over $5,4M Euros to the SGC over a five-year period. The Board has one representative from each Member and an independent Chair, who serves one 5-year term. The current Chair is Anke Müller-Fahrnow (Germany), and previous Chairs have been Michael Morgan (U.K.), Wayne Hendrickson (U.S.A.), Markus Gruetter (Switzerland) and Tetsuyuki Maruyama (Japan). The founding and current CEO is Aled Edwards (Canada). The founding Members of the SGC Company were the Canadian Institutes of Health Research, Genome Canada, the Ontario Research Fund, GlaxoSmithKline and Wellcome Trust. The current (March 2022) Members comprise Bayer Pharma AG, Bristol Myers Squibb, Boehringer Ingelheim, the Eshelman Institute for Innovation, Genentech, Genome Canada, Janssen, Merck KGaA, Pfizer, and Takeda.
SGC research activities take place in a coordinated network of university-affiliated laboratories – at Goethe University Frankfurt, Karolinska Institutet, McGill University, and the Universities of North Carolina at Chapel Hill and Toronto. The research activities are supported both by funds from the SGC Company as well as by grants secured by the scientists affiliated with the SGC programs. At each university, the scientific teams are led by a Chief Scientist, who are Stefan Knapp (Goethe University Frankfurt), Michael Sundstrom (Karolinska Institutet), Ted Fon (McGill University), Tim Willson (University of North Carolina at Chapel Hill), and Cheryl Arrowsmith (University of Toronto). The SGC currently comprises ~200 scientists.
Structural biology of human proteins – The SGC has so far contributed over 2000 protein structures of human proteins of potential relevance for drug discovery into the public domain since 2003. [17] Structures that constitute complexes with synthetic small molecules is aided by a partnership with the Diamond synchrotron in Oxfordshire. [18] The chemical probe program prioritizes (members of) protein families that are relatively understudied, or which may be currently relevant to human biology and drug discovery. These families include epigenetic signaling, [19] [20] solute transport, [21] [22] protein proteostasis, [23] [24] [25] [26] [27] and protein phosphorylation. [12] [28] [29] The protein family approach is supported by publicly available bioinformatics tools (ChromoHub, [30] UbiHub [31] ), family-based protein production and biochemistry, crystallography and structure determination, biophysics, and cell biology (for example target engagement assays). The SGC has (so far) contributed ~120 chemical probes [10] [32] [33] into the public domain over the past decade, and >25,000 samples of these probes have been distributed to the scientific community. The chemical probes conform to the now community-standard quality criteria created by the SGC and its collaborative network. [10] [34] [35] [36] [37] [38]
The Structure-guided Drug Discovery Coalition (SDDC) comprises the Seattle Structural Genomics Center for Infectious Disease (SSGCID), the Midwest Center for Structural Genomics, the Center for Structural Genomics of Infectious Diseases (CSGID), and drug discovery teams from academia and industry has resulted in 7 early drug leads for tuberculosis (TB), malaria, and cryptosporidiosis. The SDDC receives funding from participating academic initiatives and the Bill & Melinda Gates Foundation.
The University of North Carolina at Chapel Hill and the Eshelman Institute for Innovation, launched Rapidly Emerging Antiviral Drug Development Initiative (READDI™) and Viral Interruption to Medicines Initiative (VIMI™). REDDI™ is modelled after the non-profit drug research and development Drugs for Neglected Diseases Initiative (DNDi). READDI™ and VIMI™ are non-profit, open science initiatives that focus on developing therapeutics for all pandemic-capable viruses. [52]
Open science is a key operating principle. [53] A Trust Agreement [4] [5] [6] [54] is signed before reagents are shared with researchers. These reagents include cDNA clones (Addgene), chemical probes, [55] and 3D structures. [17] Tools to promote open science include open lab notebooks. [9] The latter platform is being used to share research on (for example) Diffuse intrinsic pontine glioma (DIPG), Fibrodysplasia ossificans progressiva, Huntington’s disease, [8] [56] Parkinson’s disease, and Chordoma.
The for-profit spin-off companies M4K Pharma (Medicines for Kids), M4ND Pharma (Medicines for Neurological Diseases) and M4ID Pharma (Medicines for Infectious Diseases) do not file patents and practise open science. The M4 companies are wholly owned by a Canadian charity Agora Open Science Trust whose mandate is to share scientific knowledge and ensure affordable access to all medicines. M4K Pharma has the most advanced open drug discovery program [14] and is supported with funding from the Ontario Institute for Cancer Research, The Brain Tumour Charity, Charles River Laboratories and Reaction Biology, and with contributions from scientists at the Universities of McGill, North Carolina, Oxford, Pennsylvania, and Toronto and in the Sant Joan de Déu hospital, the University Health Network hospitals, the Hospital for Sick Children, and The Institute for Cancer Research. M4K Pharma is developing a selective inhibitor of ALK2 for DIPG, a uniformly fatal pediatric brain tumour. [14]
In 2000, a group of companies and Wellcome conceptualized forming a Structural Genomics Consortium to focus on determining the three-dimensional structures of human proteins. [1] The consortium must place all structural information and supporting reagents into the public domain without restriction. This effort was designed to complement other structural genomics programs in the world.
The SGC scientific program was launched, with activities at the Universities of Oxford and Toronto, and with a mandate to contribute >350 human protein structures into the public domain. To be counted toward these goals, the proteins had to derive from a pre-defined list and the protein structures were required to meet pre-defined quality criteria. The quality of protein structures was and continues to be adjudicated by a committee of independent academic scientists. Michael Morgan was the Chair of the SGC Board, and the scientific activities were led by Cheryl Arrowsmith (Toronto) and Michael Sundstrom (Oxford). In mid 2005, VINNOVA, the Knut and Alice Wallenberg Foundation and the Foundation for Strategic Research (SSF) established the Swedish research node of the SGC. Experimental activities started at the Karolinska Institutet in Stockholm, led by Pär Nordlund and Johan Weigelt. Together, the three SGC laboratories contributed 392 human protein structures into the public domain. A pilot program in the structural biology of proteins in the malaria parasite was also initiated. [57]
The new goal for structures was 650. The SGC focused considerable activities in the areas of ubiquitination, protein phosphorylation, small G-proteins and epigenetics, and also initiated an effort in the structural biology of integral membrane proteins. In this phase, the SGC determined the structures of 665 human proteins from its Target List. With support from Wellcome and GSK, the SGC launched a program to develop freely-available chemical probes to proteins involved in epigenetic signalling which at the time were under studied. [2] [5] The quality of each chemical probe was subject to two levels of review prior to their dissemination to the public. The first was internal, through a Joint Management Committee comprising representatives from each member organization. The second was provided by a group of independent experts selected from academia. This level of oversight is aimed at developing reagents that support reproducible research. [58] [59] [13] It ultimately led to the creation of the Chemical Probes Portal. The SGC Memberships expanded to include Merck, Sharpe and Dohme, and Novartis. Wayne Hendrickson served as the Chair of the SGC Board.
The SGC mandate diversified to include 200 human proteins including 5 integral membrane proteins and chemical probes (30). Many of the chemical probes’ programs were undertaken in partnership with scientists in the pharmaceutical companies, which made the commitment to contribute the collaborative chemical probe into the public domain, without restriction. In Phase III, the SGC, along with the SSGCID (https://www.ssgcid.org/) and the CSGID (https://csgid.org/) launched the SDDC. SGC Memberships: AbbVie, Bayer AG, Boehringer Ingelheim, Eli Lilly and Janssen. Merck, Sharpe and Dohme and the Canadian Institutes for Health Research left the consortium. Markus Gruetter became the Chair of the SGC Board.[ citation needed ] [60]
This phase built on the goals of previous phases but included well-characterized antibodies to human proteins. The SGC initiated a concerted effort to develop disease-relevant, cell-based assays using (primary) cells or tissue from patients. This phase saw the launch of research activities at Goethe University in Frankfurt, at McGill University, and at the Universities of Campinas and North Carolina, and participation in ULTRADD and RESOLUTE [21] [22] within IMI. SGC Memberships: Merck KGaA, the Eshelman Institute for Innovation, Merck, Sharpe and Dohme joined while GSK and Eli Lilly left. Tetsuyuki Maruyama became the Chair of the Board.[ citation needed ]
Target 2035 is an open science movement with the goal of creating chemical [12] [24] [29] [32] [33] and/or biological [13] [59] tools for the entire proteome by 2035. [61] The launch in November 2020 and monthly webinars have and continue to be free to attend. Supporting projects currently underway include the SGC’s epigenetics chemical probe program, [62] [63] [64] the NIH’s Illuminating the Druggable Genome initiative for under-explored kinases, GPCR’s and ion channels, [65] [66] [67] IMI’s RESOLUTE project on human SLCs, [22] and IMI's Enabling and Unlocking Biology in the Open (EUbOPEN). These teams are linked to SGC’s global collaborative network. [2] [10] [35] [51] [68] [13] [59]
A biological target is anything within a living organism to which some other entity is directed and/or binds, resulting in a change in its behavior or function. Examples of common classes of biological targets are proteins and nucleic acids. The definition is context-dependent, and can refer to the biological target of a pharmacologically active drug compound, the receptor target of a hormone, or some other target of an external stimulus. Biological targets are most commonly proteins such as enzymes, ion channels, and receptors.
Chemical biology is a scientific discipline between the fields of chemistry and biology. The discipline involves the application of chemical techniques, analysis, and often small molecules produced through synthetic chemistry, to the study and manipulation of biological systems. In contrast to biochemistry, which involves the study of the chemistry of biomolecules and regulation of biochemical pathways within and between cells, chemical biology deals with chemistry applied to biology.
Chemogenomics, or chemical genomics, is the systematic screening of targeted chemical libraries of small molecules against individual drug target families with the ultimate goal of identification of novel drugs and drug targets. Typically some members of a target library have been well characterized where both the function has been determined and compounds that modulate the function of those targets have been identified. Other members of the target family may have unknown function with no known ligands and hence are classified as orphan receptors. By identifying screening hits that modulate the activity of the less well characterized members of the target family, the function of these novel targets can be elucidated. Furthermore, the hits for these targets can be used as a starting point for drug discovery. The completion of the human genome project has provided an abundance of potential targets for therapeutic intervention. Chemogenomics strives to study the intersection of all possible drugs on all of these potential targets.
Aled Morgan Edwards is the founder and Chief Executive of the Structural Genomics Consortium, a charitable public-private partnership. He is Professor of Medical Genetics and Medical Biophysics at the University of Toronto, Visiting Professor of Chemical Biology at the University of Oxford, and Adjunct Professor at McGill University.
Cheryl H. Arrowsmith is a Canadian structural biologist and is the Chief Scientist at the Toronto laboratory of the Structural Genomics Consortium. Her contributions to protein structural biology includes the use of NMR and X-ray crystallography to pursue structures of proteins on a proteome wide scale.
A protein kinase inhibitor (PKI) is a type of enzyme inhibitor that blocks the action of one or more protein kinases. Protein kinases are enzymes that phosphorylate (add a phosphate, or PO4, group) to a protein and can modulate its function.
Mitogen-activated protein kinase 7 also known as MAP kinase 7 is an enzyme that in humans is encoded by the MAPK7 gene.
LY294002 is a morpholine-containing chemical compound that is a potent inhibitor of numerous proteins, and a strong inhibitor of phosphoinositide 3-kinases (PI3Ks). It is generally considered a non-selective research tool, and should not be used for experiments aiming to target PI3K uniquely.
ChEMBL or ChEMBLdb is a manually curated chemical database of bioactive molecules with drug inducing properties. It is maintained by the European Bioinformatics Institute (EBI), of the European Molecular Biology Laboratory (EMBL), based at the Wellcome Trust Genome Campus, Hinxton, UK.
Ming-Ming Zhou is an American scientist who focuses on structural and chemical biology, NMR spectroscopy, and drug design. He is the Dr. Harold and Golden Lamport Professor and Chairman of the Department of Pharmacological Sciences. He is also the co-director of the Drug Discovery Institute at the Icahn School of Medicine at Mount Sinai and Mount Sinai Health System in New York City, as well as Professor of Sciences. Zhou is an elected fellow of the American Association for the Advancement of Science.
Chemical genetics is the investigation of the function of proteins and signal transduction pathways in cells by the screening of chemical libraries of small molecules. Chemical genetics is analogous to classical genetic screen where random mutations are introduced in organisms, the phenotype of these mutants is observed, and finally the specific gene mutation (genotype) that produced that phenotype is identified. In chemical genetics, the phenotype is disturbed not by introduction of mutations, but by exposure to small molecule tool compounds. Phenotypic screening of chemical libraries is used to identify drug targets or to validate those targets in experimental models of disease. Recent applications of this topic have been implicated in signal transduction, which may play a role in discovering new cancer treatments. Chemical genetics can serve as a unifying study between chemistry and biology. The approach was first proposed by Tim Mitchison in 1994 in an opinion piece in the journal Chemistry & Biology entitled "Towards a pharmacological genetics".
BET inhibitors are a class of drugs that reversibly bind the bromodomains of Bromodomain and Extra-Terminal motif (BET) proteins BRD2, BRD3, BRD4, and BRDT, and prevent protein-protein interaction between BET proteins and acetylated histones and transcription factors.
Targeted covalent inhibitors (TCIs) or Targeted covalent drugs are rationally designed inhibitors that bind and then bond to their target proteins. These inhibitors possess a bond-forming functional group of low chemical reactivity that, following binding to the target protein, is positioned to react rapidly with a proximate nucleophilic residue at the target site to form a bond.
Polypharmacology is the design or use of pharmaceutical agents that act on multiple targets or disease pathways.
The Chemical Probes Portal is an open, online resource whose purpose is to identify and make available high quality chemical probes for use in biological research and drug discovery. While chemical probes can be valuable tools to elucidate signal transduction pathways and to validate new drug targets, many of the probes that are in use are not selective and therefore can give very misleading results.
Jin Zhang is a Chinese-American biochemist. She is a professor of pharmacology, chemistry and biochemistry, and biomedical engineering at the University of California, San Diego.
The bump-and-hole method is a tool in chemical genetics for studying a specific isoform in a protein family without perturbing the other members of the family. The unattainability of isoform-selective inhibition due to structural homology in protein families is a major challenge of chemical genetics. With the bump-and-hole approach, a protein–ligand interface is engineered to achieve selectivity through steric complementarity while maintaining biochemical competence and orthogonality to the wild type pair. Typically, a "bumped" ligand/inhibitor analog is designed to bind a corresponding "hole-modified" protein. Bumped ligands are commonly bulkier derivatives of a cofactor of the target protein. Hole-modified proteins are recombinantly expressed with an amino acid substitution from a larger to smaller residue, e.g. glycine or alanine, at the cofactor binding site. The designed ligand/inhibitor has specificity for the engineered protein due to steric complementarity, but not the native counterpart due to steric interference.
Gerardo Turcatti is a Swiss-Uruguayan chemist who specialises in chemical biology and drug discovery. He is a professor at the École Polytechnique Fédérale de Lausanne (EPFL) and director of the Biomolecular Screening Facility at the School of Life Sciences there.
Target 2035 is a global effort or movement to discover open science, pharmacological modulator(s) for every protein in the human proteome by the year 2035. The effort is led by the Structural Genomics Consortium with the intention that this movement evolves organically. Target 2035 has been borne out of the success that chemical probes have had in elevating or de-prioritizing the therapeutic potential of protein targets. The availability of open access pharmacological tools is a largely unmet aspect of drug discovery especially for the dark proteome.
James Allen Wells is a Professor of Pharmaceutical Chemistry and Cellular & Molecular Pharmacology at the University of California, San Francisco (UCSF) and a member of the National Academy of Sciences. He received his B.A. degrees in biochemistry and psychology from University of California, Berkeley in 1973 and a PhD in biochemistry from Washington State University with Ralph Yount, PhD in 1979. He completed his postdoctoral studies at Stanford University School of Medicine with George Stark in 1982. He is a pioneer in protein engineering, phage display, fragment-based lead discovery, cellular apoptosis, and the cell surface proteome.