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NOT-RM-07-005: Solicitation of Compounds for High Throughput Screening (HTS) in the Molecular Libraries Screening Centers Network (MLSCN) Solicitation of Compounds for High Throughput Screening (HTS) in the Molecular Libraries Screening Centers Network (MLSCN)

Notice Number: NOT-RM-07-005

Key Dates
Release Date: January 10, 2007

Issued by
National Institute of Mental Health (NIMH), (http://www.nimh.nih.gov/)


This notice is a reissue and modification of Notice NOT-RM-06-017, which was published in the NIH Guide on August 2, 2006.

The National Institutes of Health (NIH) invites investigators in the public and private sectors 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 phenotypic 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 MLSCN on June 15, 2005, with the aim of generating new scientific knowledge that will translate into tangible benefits for public health.  This effort empowers multi-disciplinary academic teams to develop small molecule tools that can be used in basic and applied biological and biomedical studies.

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 benefited widely 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 phenotypic assays annually.  Assays are 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-06-545 (R03) (https://grants.nih.gov/grants/guide/pa-files/PAR-06-545.html) and  PAR-06-259 (X01) (https://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 mechanisms 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 are made available to the entire scientific community via PubChem. 

The MLSMR (http://mlsmr.glpg.com/MLSMR_HomePage/), established in September 2004, ultimately will house a collection of approximately 500,000 chemically diverse molecules, including many with proven biological activities.  It currently contains over 100,000 compounds in four categories: 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 is being 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 - https://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 important ways.

Guidance for Compounds Suitable for HTS 

In general, the MLSMR accepts fully characterized organic molecules that meet the criteria for HTS by the MLSCN.  Compounds that duplicate existing structures in the MLSMR will not be accepted, and it may be necessary to accept only subsets of large combinatorial libraries of closely related compounds.

All submitted compounds should be: at least 90% pure, sufficiently water-soluble for use in HTS, reasonably stable at room temperature, not hazardous, and provided (preferably) in solid form. Compounds obtained by high-throughput synthesis, as well as medicinal or synthetic organic chemistry are eligible.  Purified, discreet natural products from microorganisms, plants or marine organisms may also be 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.glpg.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. 

MLSMR Compound Requirements:

How to Submit Compounds

Compound 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:

Compound submission applications will be reviewed periodically (generally monthly).  Compound data files will be checked against the MLSMR Excluded Functionality filters.  Compounds that bear excluded 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 have met MLSMR requirements, as well as a list of any compounds that did not pass the filtering process.

Procedure for Compound Deposition to the MLSMR

Once compounds are 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.  Dry samples, rather than solutions, should be provided whenever possible.   A datafile that associates compound identifiers with vial barcodes must accompany the compounds.  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.

The MLSMR will perform quality control (QC) on the samples it receives by processing them according to the following protocol. Because of the high volume of analyses performed by the MLSMR, a standard QC protocol is applied to all samples.   Submitters should indicate in their proposals whether any aspects of this QC process are likely to be incompatible with the submitted compounds, and where possible, should discuss appropriate alternative analysis methods. 

  1. Weight: The MLSMR will dry the sample to a constant mass under vacuum (pressure < 5 millibar) at 25 – 35 °C.  The MLSMR will determine the net weight of the dried sample and will accept samples meeting the minimum weight requirement.
  2. Solubility: Samples must be soluble in DMSO at 10 mM.  As a first step in the compound handling process, the MLSMR will mix the sample with 2 mL of a 90:10 chloroform / methanol solvent mixture and will accept samples that dissolve completely.  For samples that fail to dissolve in the chloroform/methanol solvent mixture, the MLSMR will accept samples that dissolve completely in dimethylsulfoxide (DMSO).   
  3. Identity and Purity: The MLSMR will dry an aliquot of the chloroform / methanol (or DMSO) solution corresponding to approximately 0.05 mg dry sample.  The sample will be dissolved in 200 uL of a 97:3 methanol / DMSO solvent mixture, and this solution will be analyzed by LC-MS.  Molecular weight will be determined using positive or negative (but not both) electrospray ionization mass spectrometry.  Negative ion current is applied to compounds bearing carboxylic, sulfonic, or phosphoric acid moieties.  The MLSMR will accept samples where the target molecular ion is correctly identified to within ± 0.5 amu.  Purity will be determined by relative area under the curve (AUC) using UV (214 nm) and evaporative light scattering (ELS) detection.  The MLSMR will accept samples where the sample purity is at least 90% by UV (214 nm) and/or ELSD.

Compounds that do not pass QC for weight, solubility, identity, or purity cannot be accepted into the MLSMR and will be returned to the submitting investigator. 

Further information on compound submission and additional details on the MLSMR QC process can be found at http://mlsmr.glpg.com/MLSMR_HomePage/submitcompounds.html.


In order to offset costs associated with preparation of compounds for submission to the MLSMR (e.g. weighing, packaging, data file generation, etc.), the Molecular Libraries Initiative will provide compensation at a rate of $15 for 10mg and $10 for <10mg of each unique compound  that passes initial filtering and subsequent QC and is accepted into the MLSMR.  Funds will be distributed to compound submitters through purchase orders issued by the MLSMR contractor, BioFocus DPI.  Payment is dependant upon final acceptance of the compounds as well as full execution of NIH Roadmap Molecular Libraries Initiative Material Transfer Agreement and acceptance of BioFocus DPI purchase order.  


Initial Filtering and Review: 2-4 weeks after datafile submission
QC Completion and Final Acceptance: 4-8 weeks after receipt of compound vials at the MLSMR
Distribution to MLSCN Screening Centers: generally no more than 3 months after final acceptance

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 the 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 “MLSCN Project Team Policy on Data Sharing and IP in the MLSCN Program” (http://www.nimh.nih.gov/dnbbs/datasharing-ip.pdf). 


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

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