MLP Glossary
Table of Contents
- Scientific Terms used by the MLPCN
- Other Relevant Terms
- MLP Databases
- MLP Initiatives
- NIH Mechanisms
- MLP Governance
Scientific Terms used by the MLPCN
Assay Development: Target identification, assay design, HTS design
Chemistry validation/confirmation: May include all or one of the following: obtaining dry compound from vendor for re-assay, confirming structure of compound by LC-MS and/or NMR etc., and resynthesis of compound if necessary
Confirmatory Assays: Confirm actives to generate hits using primary assay. Includes replicate runs and dose response using primary screening assay. This may involve cherry picking hits from primary screen
HTS Implementation: HTS optimization, modification, miniaturization, intra- and inter-day run variability
HTS Validation: Replicate pilot screens of small compound libraries
Primary screening: Initial screen of compound library, usually single dose, to identify active compounds
Profiling Assays: Evaluate selectivity/specificity of hits (e.g., other members of receptor or kinase family)
Secondary Assays: Measure activity of target in different assay than primary screen, assess agonism vs. antagonism, confirm rank order of compound potencies/affinities (e.g., primary: binding assay; secondary: signaling assay)
Probe Definition v2.0 (MLSCN SC, 2007): An MLSCN probe is a compound which represents an improvement over the existing art. Supporting information is required showing currently available probes, their properties and how the new probe is clearly an improvement [first or best in class]
Potency: Criteria for potency is context dependent, varying with the assay and target type, and current state of the art. In general, probes identified via biochemical assays are expected to exhibit potencies of <500nM and, more ideally in the 100nM range. Those identified in cell based assays are expected to exhibit potencies at a level of <1microM, however in certain instances potencies in the 10microM may be acceptable. Criteria for whole organism screening is less stringent.
Solubility: Sufficient solubility in relevant solvents
Availability: The probe molecule should be accessible in amounts to allow advanced studies (15-20mg), and protocols for its preparation or isolation should be made available
SAR, mode of action: (e.g. evidence of binding to target, characterization of mechanism of action) and awareness of selectivity against relevant and/ or related targets is expected
Appropriate data on toxicity, permeability, etc. of probes are strongly encouraged
Phenotypic Screen Probe Definition 1.0 (MLSCN SC, 2007): A MLSCN probe is a compound which represents an improvement over the existing art. Supporting information is required showing currently available probe, their properties and how the new probes is clearly an improvement
Potency: Criteria for potency is context dependent, varying with the assay and target type, and current state of the art. For a phenotypic screen, potency is expected to be in at least the 1microM range
Solubility: Sufficient solubility in relevant solvents
Availability: The probe molecule should be accessible in amounts to allow advanced studies (15-20mg), and protocols for its preparation or isolation should be made available
Data on the putative target or pathway hit is required, as is selectivity data and, when feasible. In vitro assay data to rule out potential known targets.
Relevant data (e.g. cell-based, organism-based) on toxicity is required for phenotypic screens.
Permeability data or data on access of probes to site of action is expected
It is possible to identify multiple probes from one phenotypic assay; data must be available to distinguish them.
See also: Glossary of Quantitative Biology Terms from the NIH Chemical Genomics Center
Other Relevant Terms
Assay PI/Assay Provider: Investigator who submits an assay project to the MLPCN
Center PI: Primary Investigator at one of the MLPCN Centers
Science Officer: NIH staff member assigned to a specific assay project in the MLPCN. Acts as a liaison between NIH, the Center PI and the Assay PI.
Types of MLP Centers ( also see MLPCN for more detailed information)
Comprehensive Centers: The Comprehensive Centers will provide rapid screening on a broad diversity of assays and detection platforms (e.g., enzymes/proteases, G-protein coupled receptors, kinases, cytotoxicity, protein-protein interactions, protein misfolding/degradation, high-content screening, transcription/expression, etc.). These large, ultrahigh-throughput screening centers will contain all the necessary functions to take a project through the complete chemical probe development process from assay development to chemical synthesis of potent and selective probe compounds. The key functionalities or cores required by these centers are: assay development, assay adaptation/implementation, HTS, informatics and chemistry. A Comprehensive Center will be run under process management where production rate, program efficiency and costs will be carefully monitored by NIH program staff. Each center is expected to screen a library of 300K-500K compounds per assay and to process 25 or more assays per year.
Specialized Screening Centers: These centers will be smaller in scope, intended to focus on a specific type of assay or platform, and expected to complete a limited number of assays per year (about 5). These centers will have assay development, assay adaptation/implementation, screening and informatic functional cores. They will accept assays from the scientific community, as well as generate their own assays.
Specialized Chemistry Centers: Specialized Chemistry Centers will perform cheminformatics, synthetic medicinal chemistry and limited pharmacology to advance active compounds identified by the Specialized Screening Centers or, in some instances, in the Comprehensive Centers. It is essential that compounds identified as research tools for the investigation of particular targets and biological processes by the MLPCN are reliable and capable of providing valid information on the activity of their intended targets. The probe compounds produced by the centers will need to be usable by the research community for in vitro and/or in vivo studies. In most cases, compounds identified by initial screening (“hits”) will not be ideal as research tools. It is likely that properties such as affinity, specificity, and solubility will need to be improved through the combined effort of the chemistry resources of the Specialized Chemistry Center and rescreening of new compounds by the Specialized Screening Center.
MLP Databases
PubChem - PubChem is public database that provides information on the biological activities of small molecules. It is a component of NIH’s Molecular Libraries Roadmap Initiative.
PubChem BioAssay - The PubChem BioAssay Database contains bioactivity screens of chemical substances described in PubChem Substance. It provides searchable descriptions of each bioassay, including descriptions of the conditions and readouts specific to that screening procedure. The MLSCN centers are depositors for the PubChem BioAssay.
PubChem Substances - PubChem Substances Database contains descriptions of chemical samples, from a variety of sources, and links to PubMed citations, protein 3D structures, and biological screening results that are available in PubChem BioAssay. The structures from MLSMR compound collections are available in PubChem Substances under depositor name “MLSMR.”
Molecular Imaging Contrast Agent Database (MICAD) - MICAD is an online source of information on in vivo molecular imaging agents based on recommendations from the extramural community. The database includes but is not limited to agents developed for positron emission tomography (PET), single photon emission computed tomography (SPECT), magnetic resonance imaging (MRI), ultrasound (US), computed tomography (CT), optical imaging, planar radiogragphy, and planar gamma imaging. It contains textual information, references, numerous links to MEDLINE, and additional related resources at the National Center for Biotechnology Information (NCBI) and elsewhere.
MLP Initiatives
MLPCN - The Molecular Libraries Probe Production Centers Network funded through the NIH Roadmap for Medical Research. The network is part of the Roadmap’s “New Pathways to Discovery” initiative, which has set out to advance the understanding of biological systems and build a better “toolbox” for medical researchers in the 21st century. The network is funded by all of the institutes of the NIH and co-administered by the National Institute of Mental Health (NIMH) and the National Human Genome Research Institute (NHGRI) on behalf of NIH. The operation of the network is overseen by a Project Team made up of staff from NIH’s 27 Institutes and Centers.
PubChem — PubChem is a public database with annotated information about the biological activities of compounds in the Molecular Libraries Small Molecule Repository (MLSMR) as well as compound probe information.
Molecular Libraries Small Molecule Repository (MLSMR) – The NIH Molecular Libraries Small Molecule Repository collects compounds for high throughput biological screening and distributes them to the Molecular Libraries Probe Production Centers Network.
Assay Development – This initiative supports the development of a continuously evolving stream of outstanding assays that can be miniaturized, automated and further used within the Molecular Libraries Probe Production Centers Network for screening, disseminating information about small molecule-target interactions, and discovering novel molecular probes. Another aim of this effort is to enable the design of pharmacologic tools to explore cellular and physiological functions.
Chemical Diversity - This area supports the development of new and diverse chemical libraries for screening in the MLPCN centers, as well as new methods for producing, isolating, characterizing, and modifying natural products.
Instrumentation - This area supports the development of new instrumentation and devices for high-throughput screening. Miniaturization and novel methods of detection of chemical/target interactions are currently supported by this initiative.
NIH Mechanisms
X01 - A NIH mechanism of support for access to the Molecular Libraries Probe Production Centers Network (MLPCN). The Resource Access X01 application and award process is a competitive process by which NIH will select assays for implementation in the MLPCN.
R03 – The R03 award will support small research projects that can be carried out in a short period of time with limited resources. Investigators wishing to apply for an R03 grant should be aware that not all NIH Institutes and Centers (ICs) accept investigator-initiated R03 applications and that the different ICs may have specific purposes for which they use this funding mechanism.
R21 - The R21 is intended to encourage exploratory/developmental research projects by providing support for the early and conceptual stages of development. Investigators wishing to apply for an R21 grant should be aware that not all ICs accept investigator-initiated R21 applications. Investigators are strongly encouraged to consult the list of participating ICs. Applicants should also be aware that non-participating ICs might solicit R21 applications using Requests for Applications (RFAs) or Program Announcements (PAs) to meet specific program needs. Information about such initiatives can be obtained in the NIH Guide for Grants and Contracts at http://grants.nih.gov/grants/guide/index.html and by consulting with NIH staff.
U54 - The NIH U54 is a cooperative agreement award mechanism. In the cooperative agreement mechanism, the Principal Investigator retains the primary responsibility and dominant role for planning, directing, and executing the proposed project, with NIH staff being substantially involved as a partner with the Principal Investigator, as described in the, “Cooperative Agreement Terms and Conditions of Award (CTSA)”. CTSA awardees will work with NIH staff to ensure that milestones can be achieved within the budget periods of the award. If milestones are not met, funding can be limited until the milestones have been achieved.
P20 - The P20 exploratory grant is designed to support planning for new programs, expansion or modification of existing resources, and feasibility studies to explore various approaches to the development of interdisciplinary programs that offer potential solutions to problems of special significance to the mission of the NIH. These exploratory studies may lead to specialized or comprehensive centers.
MLP Governance
NIH MLPCN Project Team: The NIH MLPCN Project Team is a trans-NIH body overseeing and coordinating MLPCN activities. Project Team membership includes one or more representative(s) from each of the NIH Institutes and Centers participating in the Molecular Libraries and Imaging Initiative. Program Officials, Scientific Program Managers and Network Science Officers can be members of the NIH MLPCN Project Team. Each participating NIH Institute and Center holds a single vote on the Project Team, no matter how many members from the Institute or Center are involved. The Project Team Leader is chair of meetings and serves as the Project Team Director of the MLPCN centers on behalf of the NIH MLSCN Project Team. The Project Team receives recommendations from the MLSCN Steering Committee and will be overseen by the Molecular Libraries and Imaging Implementation Group (MLIIG).
MLSCN Steering Committee: The MLSCN Steering Committee is the operational group responsible for coordination of the activities of the MLPCN screening centers and the committee through which the NIH MLPCN Project Team interacts with the MLPCN Network. The MLPCN Steering Committee identifies scientific and policy issues that need to be addressed at the Network level, develop recommendations to the NIH MLPCN Project Team for addressing such issues, coordinate the primary recommendations for assay distribution within the Network, and coordinate the dissemination of screening data, assay protocols, and other materials with the wider scientific community.
Molecular Libraries and Imaging Implementation Group (MLIIG): The MLIIG is co-chaired by Jeremy Berg, Ph.D. (NIGMS), Mark Guyer, Ph.D. (NHGRI) and Thomas Insel, Ph.D. (NIMH) and is composed of representatives from each of the participating NIH Institutes, Centers, and Offices, including the principal leads designated by the co-chairs. The MLIIG develops and implements approved initiatives, identifies emerging issues that may warrant revisions of the implementation plan, and proposes concepts for new initiatives. Specific approved initiatives are managed by Project Teams.
