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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). NOT-RM-06-017

Follow the instructions below to submit compounds to the MLSMR, or download the instructions as pdf.

Procedure for Submitting Compounds to MLSMR

Compounds submitted to the NIH Molecular Libraries Small Molecule Repository (MLSMR) must weigh at least 5 milligrams, be soluble in DMSO, be at least 90% pure, not overlap with samples already in the MLSMR collection, and not contain certain atoms or functional groups. Below is the standard procedure to submit compounds to MLSMR.

  1. Submit Data
    1. Send to MLSCNcmpd@mail.nih.gov a datafile of the compounds that you want to submitted to MLSMR. The datafile must contain the chemical structure and your unique text identifier for each compound. Include in the chemical structure the parent compound along with any salts, hydrates, solvents, or ligands. Your compound text identifier must be contained in a field named Compound_ID. Compound_ID is the identifier for the structure (including salts, hydrates, etc.) and not the batch / lot / sample identifier.
    2. The preferred datafile is a Structure Data File (SDF). SDFs are generated by many applications, including CambridgeSoft ChemFinder, MDL ISIS and Isentris, and SciTegic Pipeline Pilot. For information on SDF format see http://www.mdli.com/downloads/public/ctfile/ctfile.jsp. Download an example sdf.
    3. The alternate datafile is a tab delimited (.tdt or .txt) text file with the structure in Daylight SMILES format. For information on SMILES see http://daylight.com/smiles/index.html. SMILES can be generated in CambridgeSoft ChemDraw and other applications. Download an example acceptable text file. See Specification and Instructions For Generating Acceptable Text File.
    4. Include all known compound hazard information in the datafile.

  2. Compound Evaluations
    1. Upon receipt of your datafile, MLSMR will evaluate the submitted structures for (a) overlap with compounds already in the MLSMR collection, and (b) presence of moieties specified in the MLSMR Excluded Functionality Filters.
    2. NIH will review the analysis of your compounds and authorize MLSMR to acquire your compounds.

  3. Compound Transfer. MLSMR will request your compounds that NIH authorized for acquisition.
    1. Samples. MLSMR will ship to you barcoded, tared 4 mL glass vials for the selected samples. Transfer your samples into the vials. Weigh each sample as a dry solid or concentrate the sample to dryness after transfer in a volatile solvent or solvent mixture. MLSMR will not typically accept samples delivered as solutions in a solvent or solvent mixture. Each sample must weigh between 5.00 and 20.00 mg.
      1. Samples must be purified by a method that removes impurities that will not elute in reverse-phase HPLC.
    2. Data. 
      1. Production Worksheet: MLSMR will send a table in electronic format containing a list of barcodes and tare weights for the supplied vials. This file is supplied as a resource and use of this data is optional.
      2. Template Data File. MLSMR will send a sample table in a specific electronic format listing your compound identifier for the samples to be supplied; a separate table will list the barcodes of the supplied vials. Populate the sample table with the vial barcode, sample / batch / lot identifier, and other data as applicable for each compound. In order for MLSMR to accept your sample, the Compound_ID entered into the Template Data File must match the Compound_ID in your original data submission. This table must be completed and returned to MLSMR with the shipped samples. If the submitted data is incomplete or incorrect, MLSMR will be unable to process the samples accordingly.
      3. QC Data. You may supply analytical data for each sample submitted to MLSMR.  If your sample does not pass the MLSMR Quality Control (QC) test for Identity and Purity, then MLSMR may consider your analytical data in determining whether to accept your sample.
        1. Datafile Format. Data must be in PDF. All data for each sample must be in a single PDF document, which may contain data from multiple analytical methods. It is highly preferred that each sample have its QC data in a separate PDF document. A PDF document containing data for multiple samples is acceptable, but processing this file may cause delays in evaluation and acceptance of the samples.
        2. Datafile Name. Give each PDF document a unique name with the formula 'SUPPLIER_PART' (e.g., 'Woodward_123abc-56'). 'SUPPLIER' is any identifier of your choosing that identifies you; 'SUPPLIER' must be the same for all PDFs submitted together. 'PART' must match the value found in the  ‘PART’ field of the MLSMR Data Template file sent with compound samples.  Neither ‘SUPPLIER’ nor ‘PART’ may contain space or underscore characters.
        3. Acceptable QC Data.  QC data must be of the purified sample and representative of the delivered sample ; and, must come from analyses conducted within 90 days of sample receipt by MLSMR. Machine-generated QC datafiles must display the analysis date.   Where a single UV wavelength is used to indicate LC purity, the UV wavelength must be in the range of 214 – 220 nm.
    3. Material Transfer Agreement (MTA). Each donating investigator will be required to sign an MTA provided to MLSMR by NIH. A template of the compound submission MTA can be found at http://mli.nih.gov/collateral/13.pdf. Upon initial submission of a compound list, the NIH will send the submitting investigator an MTA for signature by an authorized representative. Upon signature, the MTA should be returned to NIH for final execution. Compound submitters will be notified once the MTA has been fully executed. MLSMR cannot accept samples without appropriate completion of the MTA.
    4. Shipment to MLSMR. Ship the vials and datafile to MLSMR using the pre-paid shipment materials. The datafile may be delivered by email to CpdMgmt@glpg.com, or on a CD or DVD.

  4. Sample Quality Control (QC). The MLSMR sample QC procedure is summarized here. MLSMR accepts samples that pass the Mass, Solubility, and Identity / Purity QC tests. For a more complete description of the procedure see the Quality Control (QC) Procedure.
    1. Mass: MLSMR will dry the sample to a constant mass, measure the vial gross weight, and determine the sample net weight. MLSMR accepts samples with mass between 5.00 and 20.00 mg. See the complete Sample Mass Procedure.
    2. Solubility: MLSMR must completely solubilize the sample in order to distribute it for HTS. Each sample will be tested for solubility in one or more solvents or solvent mixtures. MLSMR accepts completely soluble samples. See the complete Sample Solubility Procedure.
    3. Identity and Purity: MLSMR will determine the identity and purity of each sample by LC-MS with UV or ELS detection. Samples with the correct mass and at least 90% AUC by UV or ELS are accepted. See the complete Sample Identity and Purity Procedure.
    4. Non-conforming samples: MLSMR will inform you of samples that do not meet any of the QC criteria. Upon agreement with you, MLSMR will implement one of the following options for these samples:
      1. MLSMR will return the sample to you at MLSMR's expense; or
      2. MLSMR will dispose of the sample.

  5. PubChem Registration. MLSMR will register accepted samples in PubChem, the NCBI database of small molecules and biological data.
  6. Sample Distribution. MLSMR will distribute accepted samples to MLSCN screening centers for use in High Throughput Screening. Biological assay results are posted in PubChem. Samples are distributed to the MLSCN centers on a quarterly basis.

Quality Control (QC) Procedure

  1. Sample Mass
    1. Process: MLSMR will conduct the following QC procedure to determine the mass of the sample.
      1. Sample received in MLSMR's container: MLSMR will dry the sample to a constant mass under vacuum (pressure < 5 millibar) at room temperature. MLSMR will determine the net weight of the sample by weighing the dried sample and subtracting the tare weight of the vial.
      2. Sample received in supplier's container: MLSMR will dry the sample to a constant mass under vacuum (pressure < 5 millibar) at room temperature. MLSMR will determine the sample mass by transferring the sample to an MLSMR container.
    2. Mass Pass / Fail Determination: samples will fail if the sample net weight is less than 5.00 or greater than 20.00 mg. If the sample fails the mass criterion, MLSMR will inform the supplier of a ‘Mass-failed sample’.

  2. Sample Solubility: MLSMR will test the solubility of each sample according to the procedure listed in item 2a. The solubility test will be conducted with the first solvent or solvent mixture listed in item 2c. If the sample fails the solubility test in this solvent, then the sample will be concentrated to dryness and tested in the next solvent or solvent mixture in item 2c. MLSMR will repeat the process until either (a) the sample passes the solubility test, or (b) the last solvent in 2c has been tested, in which case the sample will fail the solubility test.
    1. Solubility test procedure
      1. MLSMR will add 2.5 ± 0.5 mL of a solvent or solvent mixture to each container. MLSMR will cover each container and place it on an orbital shaker, which will shake the vial (parameters: speed = 750 rpm; pulsing = 20 pulses/min; duty cycle = 85%; time = 15 minutes).
      2. If the sample is not completely dissolved then MLSMR will mix the vial contents using a vortex mixer.
    2. Solubility Pass / Fail Determination: a sample will pass the solubility test if the mixture is a solution or a slightly cloudy, fine, uniform suspension. A sample will fail the solubility test if the mixture does not appear completely homogenous, or if solid material is present, or if the mixture is a suspension. If the sample fails the solubility criterion, MLSMR will inform the supplier of a ‘Solubility-failed sample’.
    3. Solvents and solvent mixtures
      1. 90:10 (v:v) Chloroform / methanol
      2. Dimethylsulfoxide (DMSO)

  3. Sample Identity and Purity: MLSMR will perform the following identity and purity check on received samples.
    1. Sample Preparation: MLSMR will dissolve the compound (approx. 0.05 mg) in a mixture of methanol (195 uL) and dimethylsulfoxide (DMSO) (5 uL).
    2. Analysis: MLSMR will analyze the sample by LC-MS. MLSMR will acquire positive electrospray ion current, UV (214 nm) absorbance, and evaporative light scattering (ELS) signals.
    3. Analysis System.
      1. Autosampler: Gilson 215 multi-probe liquid handler equipped with an 889-injection module with eight probes.
      2. LC pump: Waters 600 multi-solvent delivery system.
      3. UV detector: Waters 2488 multichannel UV/VIS detector.
      4. MS: MicroMass MUX-LCT mass spectrometer with a multiplexed electrospray ion source.
    4. HPLC conditions:
      1. Mobile phases are A: water with 0.1% acetic acid, and B: CHB3BCN with 0.1% acetic acid.
      2. Gradient is 10-100% B in 3.0 min and hold at 100% B for an additional 0.5 min.
      3. A flow (12.0 mL/min overall) is split into eight C-18 columns (50 x 2.1 mm) for analysis
    5. LC measurement: UV (214 nm) and ELSD.
    6. MS Ionization mode: ESI+ with mass range of 150 - 1500.
    7. Data Processing: Raw data is processed by Masslynx 4.0 with Openlynx software.
    8. Data Analysis: The target molecular ion is used to identify the desired product. Purity is determined by relative peak area in the chromatogram as detected by UV (214 nm) or ELS.
    9. Identity and Purity Pass / Fail Determination: samples will pass the Identity and Purity QC requirements if the sample LC purity as measured by area under the curve (AUC) is greater than or equal to 90.0% by UV (214 nm) or ELS or both; and, the target molecular ion is correctly identified within ± 0.5 amu. If the sample does not pass the Identity and Purity criteria, MLSMR will inform the supplier of an ‘Identity and Purity-failed sample’.
    10. Submitting investigators should inform MLSMR if any aspects of this quality control process are likely to be incompatible with the compounds proposed for submission, and where possible, discuss appropriate, alternative analysis methods.

Specification and Instructions For Generating an Acceptable Text File

  1. Specification: Compounds submitted for review in tab delimited text file format must contain a column with the header ‘Compound_ID’ and a column with the header ‘SMILES’. Other columns are acceptable. Each row below the headers will correspond to a compound to be evaluated, and must contain data in the Compound_ID and SMILES columns. All data in the TDT file must be in the row and column format; do not include notes or instructions in the TDT file.

  2. How to generate an acceptable TDT file: Acceptable text files may be generated by many methods. The following is an example of a method for generating an acceptable TDT file.
    1. Create a new Microsoft Excel workbook.
    2. In row 1, label column A ‘Compound_ID’ and column B ‘SMILES’.
    3. Enter the structure identifier (e.g., ‘LAB000000123’) for your first compound in the Compound_ID column of row 2.
    4. In CambridgeSoft ChemDraw, draw the structure corresponding to the Compound_ID entry in row 2.  Select the entire structure (including salts, hydrates, solvents, and the like).  On the Edit menu, select Copy As / SMILES.  Paste the SMILES string (e.g., ‘NCCC1=CNC=N1.Cl’) into the Excel spreadsheet in row 2 of the SMILES column.
    5. For each compound to be submitted repeat (c) and (d) in the next row.
    6. In Excel, select File / Save As…  Give your file a name without an extension.  In the ‘Save as type:’ dropdown menu, select ‘Text (Tab delimited) (*.txt)’.  Save the document as a .txt file.
    7. The *.txt file may be opened and edited with a variety of applications, including MS Excel, MS Word, and WordPad.