This is a Small Business Sources Sought notice. This is NOT a solicitation for proposals, proposal abstracts, or quotations. The purpose of this notice is to obtain information regarding: (1) the availability and capability of qualified small business sources; (2) whether they are small businesses; HUBZone small businesses; service-disabled, veteran-owned small businesses; 8(a) small businesses; veteran-owned small businesses; woman-owned small businesses; or small disadvantaged businesses; and (3) their size classification relative to the North American Industry Classification System (NAICS) code for the proposed acquisition. Your responses to the information requested will assist the Government in determining the appropriate acquisition method, including whether a set-aside is possible. An organization that is not considered a small business under the applicable NAICS code should not submit a response to this notice.

This notice is issued to help determine the availability of qualified companies technically capable of meeting the Government requirement and to determine the method of acquisition. It is not to be construed as a commitment by the Government to issue a solicitation or ultimately award a contract. Responses will not be considered as proposals or quotes. No award will be made as a result of this notice. The Government will NOT be responsible for any costs incurred by the respondents to this notice. This notice is strictly for research and information purposes only.

Background: The National Center for Advancing Translational Sciences (NCATS) is a part of the National Institutes of Health (NIH), which mission it is to catalyze the generation of innovative methods and technologies that will enhance the development, testing and implementation of diagnostics and therapeutics across a wide range of human diseases and conditions.
The NCATS Chemical Genomics Center (NCGC) is tasked with identifying and developing novel small molecule leads against a wide spectrum of human disease targets, which it accomplishes by screening thousands of small molecules in collaboration with both intra-and extramural researchers. A In pursuit of this goal, the Center has a strong internal transdisciplinary team of scientists who continually discover novel small molecules for application against a wide range of human diseases.
As such, discovering probe molecules that could serve as starting points for therapeutics in rare cancers is of great interest within NCATS. NCATS has several projects that address many aspects of oncology mechanisms and approaches to discovering novel, effective small molecules

Purpose and Objectives: The purpose of this requirement is to procure testing services that will provide insight on efficacy across many cancers and will help progress and provide critical scientific guidance on projects that NCATS has been working on for many years.

Project Requirements:
NCATS has a need for the production, purification and X-ray structure determination of Plasmodium falciparum Vps34 in complex with a small molecule ligand.

Vendor shall provide the following:

Scope of Work
Phase 1: Construct Evaluation: Two weeks
• produce modified expression constructs to evaluate the suitability of the selected forms in an E. coli expression system. The utility of various tags may be evaluated
• The resultant vectors will be transformed into a suitable E. coli strain. Selected clones will be tested for expression, with optimization of induction and culture conditions to evaluate for soluble expression
• The expression levels, solubility, and stability of the various constructs and expression conditions will be evaluated by SDS-PAGE and Western blot analysis.

Phase 2 : Pilot Scale purification: Two weeks
• two constructs (and expression systems) will be selected to evaluate and develop a purification process for each of the two constructs.
• If an E. coli expression system is utilized for generation of the protein, the vendor will produce a 2 L culture for use in the method development. If a yeast-based expression is selected, the vendor will utilize material available from NCATS, or produce a suitable amount.
• The protein will be characterized by SDS-PAGE, MALDI-TOF mass spectrometry, size-exclusion chromatography (SEC), and thermal stability shift.
• If requested, portion of the resultant materials will be supplied to NIH NCATS for confirmation of quality and activity

Phase 3 : Thermal Shift assay confirmation of ligand binding: Two weeks
• The vendor will develop a TSA for the provided protein and characterize the melting temperature (Tm) of the initial material.
• The vendor will perform a protein titration in the initial purification buffer to identify a protein concentration suitable for TSA screening in a 384-well plate format
• Each protein (or protein complex) will be evaluated in a thermal stability assay screen to evaluate the buffer conditions and additives that would influence the stability and signal for the protein
• The vendor will evaluate a control compound (a known binder), if available, and the test compound in the buffer conditions for optimization of the TSA screen. A six-point concentration series will be run to evaluate to binding interaction.
•
Phase 4 : Bulk protein production and purification: Two months
• Based on yields established in Phase 2, expression cultures will be produced to allow yields of >10 mg of each protein with purity ≥95%.
• The purification protocol established in Phase 2 will be scaled up to process the material provided
• The protein will be characterized by SDS-PAGE, MALDI-TOF mass spectrometry, and SEC

Phase 5 : Co-crystallization screening and optimization: Two months
• Based on a review of the available information, the target protein and the top set of ligands will be selected for the initial co-crystallization efforts
• Based on the binding interaction data, experimental conditions will be designed for the production of the complex on the milligram scale for use in the crystallographic studies
• The protein-ligand complex will be screened for crystallization with sparse-matrix and systematic grid screening approaches.
• Conditions that initially produce microcrystals will be identified
• Selected conditions will be optimized to improve the crystal size and quality.
• Based upon the forms crystallized and the priority of interest, the vendor will obtain approval for specific co-crystal(s) to be evaluated and pursued for full structure determination.
• Crystal of suitable size will be harvested, transferred into suitable cryoprotection solutions, and frozen for transport to a synchrotron X-ray facility.

Phase 6: X-ray structure determination: Two months
X-ray diffraction analysis and data collection:
• For each targeted structure, multiple crystals will be screened for X-ray data quality.
• If the X-ray diffraction is of sufficient quality (≤2.8 Å resolution and good diffraction lattice properties) then a complete X-ray data set will be obtained for the best crystal.

Initial data processing:
• Complete data sets will be indexed and scaled, followed by space group evaluation, molecular replacement, and generation of initial electron density maps
• Processed data sets will be evaluated according to statistical values and interpretation of the initial electron density map

Refinement, model building, analysis, and reporting:
• If the processed data and electron density maps are of sufficient quality and resolution, and the bound ligand is observed, then multiple rounds of refinement and model building will be performed to obtain a final model.
• The resultant model will be analyzed, and both the structure and results presented to NIH NCATS in a summary document, along with structure files

Deliverables / Reporting Requirements:
Contractor shall deliver:
1. purified protein for activity testing at the completion of Phase 2 and/or Phase 4, upon request
2. deliver a detailed report describing the methods and analytical results at each stage of the process
3. deliver crystal structures of complexes, together with the associated structure files (.pdb, .hkl, .map)

Period of Performance:
Within 8 months ARO

Capability statement /information sought. Contractors that believe they possess the ability to provide the requirement should submit documentation of their ability to meet each of the project requirements to the Contract Specialist. The response should directly and specifically state in the, capabilities statement, which project requirements you can supply. Contractors must also provide their Company Name, DUNS Number, Physical Address, Point of Contact, and Size and Type of Business (e.g., 8(a), HubZone, etc.) pursuant to the applicable NAICS code and any other information that may be helpful in developing or finalizing the acquisition requirements.

The information submitted must be must be in an outline format that addresses each of the elements of the project requirement and in the capability statement /information sought paragraphs stated herein.
The response must include the respondents' technical and administrative points of contact, including names, titles, addresses, telephone and fax numbers, and e-mail addresses.

All responses (capability statements) sent in response to this Small Business Sources Sought Notice must be submitted electronically (via e-mail) to the Contract Specialist. Facsimile responses are NOT accepted.

The response must be submitted to Stacey Polk, Contract Specialist at [email protected].

The response must be received on or before the closing date of this announcement.

"Disclaimer and Important Notes: This notice does not obligate the Government to award a contract or otherwise pay for the information provided in response. The Government reserves the right to use information provided by respondents for any purpose deemed necessary and legally appropriate. Any organization responding to this notice should ensure that its response is complete and sufficiently detailed to allow the Government to determine the organization's qualifications to perform the work.

Respondents are advised that the Government is under no obligation to acknowledge receipt of the information received or provide feedback to respondents with respect to any information submitted. After a review of the responses received, a pre-solicitation synopsis and solicitation may be published in Federal Business Opportunities. However, responses to this notice will not be considered adequate responses to a solicitation.
Confidentiality: No proprietary, classified, confidential, or sensitive information should be included in your response. The Government reserves the right to use any non-proprietary technical information in any resultant solicitation(s)."

Bid Protests Not Available