Effective Jan. 1, 2017, NCATS will no longer supply compounds and NIH Clinical Collection sets through its Small Molecule Repository (SMR). NCATS is processing SMR orders placed prior to Dec. 31, 2016, and investigators should expect delivery by no later than Jan. 31, 2017. The SMR website will remain accessible through Jan. 31, 2017, and then permanently shut down. NCATS thanks all who supported the SMR over the years.
Project > Submit Compounds
The National Institutes of
(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 Probe Production Centers Network (MLPCN).
Follow the instructions below to submit compounds to the MLSMR, or
download the instructions as ZIP file.
Procedure for Submitting Compounds to MLSMRCompounds
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.
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.
- The preferred datafile is a Structure
Data File (SDF). SDFs are generated by many applications, including CambridgeSoft
ChemFinder, MDL ISIS
and SciTegic Pipeline
information on SDF format see http://www.mdli.com/downloads/public/ctfile/ctfile.jsp.
an example sdf.
- The alternate datafile is a tab delimited (.tdt or .txt) text file with the SMILES format.
SMILES can be generated in CambridgeSoft ChemDraw and other applications.
Download an example acceptable text file.
all known compound hazard
information in the datafile.
- Compound Evaluations
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.
- NIH will review the analysis of your compounds
and authorize MLSMR to acquire your compounds.
Transfer. MLSMR will request your compounds that NIH authorized for
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.
must be purified by a method that
removes impurities that will not elute in reverse-phase HPLC.
- 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.
- Template Data
File. MLSMR will send a sample table in a specific electronic format
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.
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
analytical data in determining whether to accept your sample.
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.
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.
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.
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 https://mli.nih.gov/mli/mlpcn/documents-definitions/?dl_id=673.
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.
- 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@evotec.com,
or on a CD or DVD.
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.
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.
- 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.
- 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.
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:
- MLSMR will
return the sample to you at MLSMR's expense; or
will dispose of the sample.
- PubChem Registration. MLSMR will register
accepted samples in PubChem,
the NCBI database of small molecules and biological data.
Distribution. MLSMR will distribute accepted samples to MLPCN screening
centers for use in High Throughput Screening. Biological assay results
are posted in PubChem. Samples are distributed to the MLPCN centers on a quarterly basis.
Control (QC) Procedure
MLSMR will conduct the following QC procedure to determine the mass of
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.
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.
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
- 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.
- 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
- If the sample is not completely
dissolved then MLSMR will mix the vial contents using a vortex mixer.
- 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’.
- Solvents and solvent mixtures
(v:v) Dichloroethane / methanol
Identity and Purity: MLSMR will perform the following identity and
purity check on received samples.
Preparation: MLSMR will dissolve the compound (approx. 0.05 mg) in a
mixture of methanol (195 uL) and dimethylsulfoxide (DMSO) (5 uL).
- 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.
Gilson 215 multi-probe liquid handler equipped with an 889-injection
module with eight probes.
- LC pump: Waters 600
multi-solvent delivery system.
- UV detector:
Waters 2488 multichannel UV/VIS detector.
MicroMass MUX-LCT mass spectrometer with a multiplexed electrospray ion
phases are A: water with 0.1% acetic acid, and B: CHB3BCN with 0.1%
- Gradient is 10-100% B in 3.0 min and
hold at 100% B for an additional 0.5 min.
- A flow
(12.0 mL/min overall) is split into eight C-18 columns (50 x 2.1 mm)
measurement: UV (214 nm) and ELSD.
- MS Ionization
mode: ESI+ with mass range of 150 - 1500.
Processing: Raw data is processed by Masslynx 4.0 with Openlynx
- 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
- 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’.
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.