Solicitation of Compounds for High Throughput Screening (HTS) in the Molecular Libraries Screening Centers Network (MLSCN)
Notice Number: NOT-RM-06-017 (January 10, 2007 - Reissued as (NOT-RM-07-005).
Key Dates
Release Date: August 2, 2006
Issued by
National Institute of Mental Health (NIMH), (http://www.nimh.nih.gov/)
Purpose
The National Institutes of Health (NIH) invites investigators in the public
and private sector to submit compounds to the NIH Molecular Libraries Small
Molecule Repository (MLSMR) to be used for high throughput biological screening
(HTS) by the Molecular Libraries Screening Centers Network (MLSCN).
Our goals include 1) expansion of the MLSMR compound collection with structurally diverse compounds; 2) screening of these compounds against a variety of biochemical and cell-based assays by the MLSCN to identify and develop probes of biological function; 3) providing compound suppliers with information on the biological activities of their compounds; and 4) making information about the chemical structures and biological activities of the compounds freely accessible through PubChem (http://pubchem.ncbi.nlm.nih.gov/).
NIH seeks to encourage collaboration between chemists who provide their compounds and biologists who develop HTS assays, through their participation in activities of the MLSMR, MLSCN and PubChem resources.
MLSCN, MLSMR, and PubChem
The NIH Molecular Libraries and Imaging Roadmap initiative launched the Molecular Libraries Screening Centers Network (MLSCN) on June 15, 2005, with the aim of generating new scientific knowledge that will translate into tangible benefits for public health. This effort will empower multi-disciplinary academic teams to develop small molecule tools that can be used in basic and applied biological and biomedical studies.
High throughput screening (HTS) involves rapid screening of large numbers of compounds in a biological assay. Although HTS of small molecule libraries has been performed extensively by the pharmaceutical industry in the context of drug discovery and development, the academic community has not yet widely benefited from the considerable potential of HTS to provide investigative tools to advance the understanding of biology. This is because most academic scientists have limited access to automated screening facilities and to collections of structurally diverse compounds. The MLSCN was created to provide such resources.
The MLSCN is a collaborative research network comprising one NIH intramural screening center and nine extramural centers. The ten network screening centers are capable of running 100-200 biochemical and cell-based assays adaptable to HTS annually. Assays will be submitted by the research community in response to the Program Announcement “Solicitation of Assays for High Throughput Screening (HTS) in the Molecular Libraries Screening Centers Network (MLSCN),” PAR-06-259 (http://grants.nih.gov/grants/guide/pa-files/PAR-06-259.html). The MLSCN, along with PubChem and the MLSMR, offers a new dimension in research opportunities for chemists and biologists in the academic and non-profit sector. The sharing of small molecules, biological assays, and screening data with the larger scientific community represents a new public sector paradigm that promises to facilitate the understanding of basic biological mechanism and shorten the timeline for drug development, with resulting benefits to public health, especially for rare disorders.
PubChem (http://pubchem.ncbi.nlm.nih.gov/) is a public sector database managed by the National Center for Biotechnology Information. Screening data, including the biological activities from HTS assays generated by the MLSCN and the structures of compounds in the MLSMR will be made available to the entire scientific community via PubChem.
The MLSMR (http://mlsmr.discoverypartners.com/MLSMR_HomePage/), established in September 2004, ultimately will house a collection of approximately 500,000 chemically diverse molecules with both proven and unknown biological activities. It currently contains nearly 100,000 compounds in four categories including 1) specialty sets of pharmacologically active compounds; 2) targeted libraries for protease, kinase, GPCR, ion channel, and nuclear receptor targets; 3) diversity sets; and 4) natural products. The MLSMR compound collection will be expanded with acquisitions from the following sources: 1) commercial chemical suppliers; 2) NIH P41 grantees under the initiative entitled, “Pilot-Scale Libraries for High-Throughput Screening” (RFA-RM-06-003 - http://grants.nih.gov/grants/guide/rfa-files/RFA-RM-06-003.html); and 3) the world wide chemistry research community.
Benefits to Chemists
By submitting samples of compounds to the MLSMR, contributing investigators may benefit in some important ways.
Guidance for Compounds Suitable for HTS
In general, the MLSMR accepts fully characterized organic molecules from all sources that meet the criteria for repository compounds for HTS. Compounds that duplicate existing structures in the Repository will likely not be accepted and it may be necessary to accept only subsets of large combinatorial libraries of closely related compounds.
All submitted compounds should have as the following properties: purity of at least 90%, adequate aqueous solubility for use in HTS, reasonable stability at room temperature, not hazardous, and preferably in solid form. Acceptable compounds, for instance, include compounds synthesized by high-throughput synthesis, and products of medicinal or synthetic organic chemistry. Purified natural products from microorganisms, plants or marine organisms are also suitable for biological screening.
While libraries submitted in response to this initiative need not be “drug-like” in the usual sense (since NIH’s goal is not drug discovery), chemical stability under HTS and storage conditions is very important. Also, compounds with inherently reactive functional groups (see, http://mlsmr.discoverypartners.com/MLSMR_HomePage/identify.html) as well as compounds that are prone to nonspecific aggregation (see, for example, J. Med. Chem. 2003, 46, 4265-4272) are not considered suitable for this solicitation.
How to Submit an Application
Compounds submissions will be accepted on a rolling basis. Any investigator who wishes to submit compounds to the MLSMR should submit the following data electronically, via email to MLSCNcmpd@mail.nih.gov with the submitter’s name (last name, first name) on the Subject line:
Review Procedure
MLSMR Compound Requirements:
Selection Process:
Compound submission applications will be accepted on a rolling basis and will be reviewed periodically (generally bimonthly). Compound data files will be checked against the MLSMR Excluded Functionality filters. Compounds that are identified by the filters as including reactive functionality will not be selected for inclusion in the MLSMR. After this review, compound submitters will be provided with a list of the compounds that met all requirements and which have been selected for inclusion in the MLSMR, as well as a list of any compounds that did not pass the filter process.
Procedure for Compound Deposition to SMR
Once a compound(s) is selected, the MLSMR will provide the compound submitter with pre-tared, barcoded 4mL glass vials for packaging and transport. The compound submitter will fill the vials and return them to the MLSMR. Samples should be provided as dry, and not as solutions in a solvent or solvent mixture whenever possible. A datafile that associates compound identifiers with vial barcodes must accompany the compound(s). The MLSMR will confirm safe arrival by email. Relevant properties of the submitted compounds will be registered and entered by the MLSMR into a database. Transportation charges will be paid by the NIH.
MLSMR will perform Quality Control on the samples it receives by processing them according to the following protocol.
Compounds that do not pass Quality Control for weight, solubility, or identity and purity cannot be accepted into the MLSMR and will be returned to the submitting investigator. Submitters should indicate in their proposals whether any aspects of this quality control process are likely to be incompatible with the proposed compounds, and where possible, should discuss appropriate alternative analysis methods.
Material and Data Sharing
Submitting chemists will be required to provide the structure of each compound. Investigators will be expected to sign a material transfer agreement (MTA) with MLSMR (http://www.nimh.nih.gov/dnbbs/NIH-ML-SMR-Incoming-MTA.pdf). Compounds will only be released from the MLSMR under an outgoing material transfer agreement (http://www.nimh.nih.gov/dnbbs/NIH-ML-SMR-Outgoing-MTA.pdf). Structure information on all compounds accepted into the MLSMR will be made publicly available in PubChem and all screening data generated by the MLSCN will be deposited in PubChem after they have been confirmed for accuracy. All data generated by the MLSCN will be freely available to the research community in a form that will support redisplay and reanalysis, so that maximal utility of this research resource will be realized. Additional information on MLSCN data sharing and intellectual property policies can be found in the MLSCN Project Team Policy on Data Sharing and IP in the MLSCN Program (http://www.nimh.nih.gov/dnbbs/datasharing-ip.pdf).
Inquiries
We encourage inquires concerning this Notice and welcome the opportunity to answer questions from potential submitters.
Direct your questions to:
Jamie Driscoll
Project Officer, Molecular Libraries Small Molecule Repository
National Institute of Mental Health/NIH/DHHS
6001 Executive Boulevard, Room 7187, MSC 9641
Bethesda, MD 20892-9641
Rockville, MD 20852-9641 (for express/courier service)
Telephone: (301) 443-5288
FAX: (301) 402-4740
Email: jdrisco1@mail.nih.gov
Weekly TOC for this Announcement
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