NCATS Small Molecule Repository (NCATS SMR)

National Center For Advancing Translational Sciences

Investigators

Abstract

With the end of the MLP in 2013, several resources developed as part of the Molecular Libraries needed to continue to provide material and informatics to the public. Continuation of these resources required that oversight and funding moved to individual NIH Institutes and Centers. The SMR was moved to NCATS as the Center focused on the continued translational advancement of probes for disease target identification and drug discovery. Major activities for the SMR in 2014-2015 were: 1. Transfer of management, contract and budget responsibilities from NIMH and the Common Fund to NCATS. 2. Out-dated equipment dating back to the start of the SMR needed to be refurbished or replaced. 3. In its new role as part of NCATS, the purpose of SMR needed to be redefined and a new set of objectives for the SMR needed to be developed Progress on transition to NCATS Evotec, the contractor for the SMR, was retained and contract oversight is in the process of being transferred from the NIMH COR to NCATS COR and a Contract Officer from the NIDA COAC will provide future oversight of the SMR contract. The SMR joins NCATS as part of the Division of Pre-Clinical Innovation (DPI) and the responsibility of the NCATS Intramural Scientific Director, Dr. Anton Simeonov. Under the direction of Dr. Simeonov, the SMR will support screening and discovery for NCATS DPI and provide selected compound subsets to extramural investigators. Funds were found to support the replacement of several key pieces of equipment for the SMR. The following equipment will be replaced: 1. Brooks SampleStore II- A new compound tube storage system to replace the current Unistore used to house and maintain the SMR compound collection, 2. Tecan EVO 150 Liquid Handler- A new automated liquid handling instrument to replace the existing multifunctional liquid dispensing instrument to quantitatively solubilize compounds and place in storage tubes, 3. Labcyte Echo-550 Acoustic Dispensor- A new nanoliter sample dispensing instrument to replace the existing acoustic dispenser, 4. Nanalysis NMReady 60Pro- the SMR will also receive a Bench-top high-resolution NMR instrument that will be used in conjunction with an LC-Mass Spectrometer in support of compound Quality Control analyses. The SMR needed to redefine its role in support of the NCATS intramural program and as a future provider of compounds to the extramural community. In the past year, the new role for the SMR was identified and developed as defined below. In Support of NCATS Programs: NCATS DPI programs require both broad screening in search of compounds that modify the activity of new protein targets and metabolic pathways and selective chemical structures to probe the mechanism of protein interactions. The SMR contains over 400,000 small molecule compounds that can support the broad screening requirements of DPI and also can provide informatics and chemical annotation to identify new chemical entities useful in probing biological pathways and protein interactions. Future objectives in support of NCATS programs will continue to maintain and provide compounds and work with NCATS biologists and chemists to continually improve the selection of compounds available from the repository. In Support of Extramural Investigators: To learn more about the needs of outside investigators, Evotec was asked to convene a User Feedback Panel composed of scientists from academic and industrial institutions, contractor staff and staff from several NIH Institutes. The Panel met on two separate occasions and made the following recommendations for how the SMR could best serve the research community. 1. Significant interest in bringing all or parts of the SMR collections to various institutes. 2. Dramatic shift by outside investigators away from large libraries, to small compound sets of compounds known to be bioactive. 3. Discuss making the libraries 'open source' to NIH supported investigators: a. Allow investigators to cherry pick the compounds in the repository that they want. b. Accept investigator recommendations for future compound additions to the repository. c. NIH would need to recover cost of service if it were to provide open source access. 4. Recommend adding compounds from the literature (including patents) to identify interesting, non-commercial molecules. This will require a significant chemistry commitment. 5. In addition to enabling collaborations on specific projects, NCATS staff work with Evotec to develop improved methods and technology that advance the science of Compound Management. Standard SMR Operations Achievements This Year: Over 40 MTAs covering out-going Compound Sets to investigators were signed A total of 25 orders were placed and shipped for the NIH Compound Collection (NCC) Subset of 726 bioactive compounds Both MeSH and target annotation data were compiled and added to the NCC subset Stability data collected on compounds stored in the SMR Preparation of the Probe+ Subset underway New website providing direct access to investigator to order compounds under development and will soon be publicly available. Redesigning storage format to define tautomeric differences in some compounds and correct for errors in salt forms of some compounds. Ability to Share Cost of Compound Resource with Investigators An Act of Congress in 2013 provided in GP Sec. 225, that some intramural/extramural collaborations might be facilitated if costs could be shared or reimbursed, or if other flexible funding arrangements could be established. This flexible spending approach was voted into Appropriation Law and impacted the ability of NCATS to recover costs in support of the SMR as a public resource. The recovered costs would then be used to replace the compounds when exhausted and insure the continuation of the resource. Toward this goal, an account was set up to allow collection of funds from investigators that access the SMR resource, a public website providing direct ordering of compounds by the investigator was created and a credit card payment process is under development. Plans are to begin providing compounds at cost to the public next year.