Notice Number: NOT-RM-08-026

Key Dates
Release Date:  September 5, 2008

Issued by
This notice is part of an NIH Roadmap Initiative.  All NIH Institutes and Centers participate in Roadmap Initiatives.  The information will be collected by NIMH and NHGRI on behalf of the NIH.

Purpose

The purpose of this notice is to facilitate access to MLPCN’s laboratory and technical resources for potential assay providers who intend to develop a high throughput screening (HTS) plan and grant application for the identification of small molecule probes (PAR-08-035 and PAR-08-024). 

Background
The NIH Molecular Libraries Program aims to enable the rapid transformation of new scientific knowledge into tangible benefits for public health. As a national resource, the MLPCN interfaces with other components of the Molecular Libraries Roadmap Program, including the Molecular Libraries Small Molecule Repository (MLSMR, http://mlsmr.glpg.com/MLSMR_HomePage/), and PubChem public database (http://pubchem.ncbi.nlm.nih.gov/).  The MLSMR has acquired a collection of over 300,000 compounds and will continue the acquisition up to ~500,000 compounds, from both commercial and academic sources, with well-known or unknown biological activities and diverse chemical structures. The program is designed to utilize these small molecule compounds to catalyze scientific breakthroughs that will contribute to the identification of molecular entities or molecular classes that may facilitate basic research by the scientific community and accelerate the development of therapeutics.

The MLPCN has state-of-the-art screening platform technologies capable of running almost any biochemical or cell-based assay of targets including enzyme, cell signaling pathway, protein-protein interaction, G-protein coupled receptor (GPCR), ion channel, transporter, nuclear receptor, protein-nucleotide interaction, and others.  Many of the above laboratory cuvette and culture dish-based assays are amenable to miniaturization, reformatting, and adaptation to 384- or 1,536-well microtiter plate formats for HTS in the MLPCN centers. However, there are certain technical constraints imposed by current HTS technological platforms that may limit convertibility of a bench top assay to an HTS assay. For example, an HTS-friendly assay typically prefers none or few  liquid addition steps during its implementation, and needs to be sensitive and robust within a small assay volume of a few to tens of microliters. To ease automation scheduling, the HTS assays are often configured as endpoint measurements via light detection of fluorescence, luminescence, and/or absorbance. There are additional technical considerations toward developing a successful HTS assay, all of which prompt the need or benefit for early interaction between assay submitters and MLPCN centers, prior to submission of an assay grant application.

MLPCN support
The MLPCN centers will provide consultation via telephone, email, or lab visit arrangement to assay submitters to assist in HTS assay development and optimization leading to a plan for the identification of chemical probes.

Centers can provide advice such as identification and selection of commercial HTS assay reagents and suitable assay format and readout.  In addition, the centers may be able to provide assistance in adapting assays to microplate format and in performing a pilot screen of a small library of compounds (e.g. the Library of Pharmacologically Active Compounds, LOPAC collection) to generate sufficient preliminary assay data to support a R03 grant application submission (PAR-08-035) by the assay provider.  Further, the potential assay providers might seek advice from the MLPCN centers about orthogonal assays to validate the hits, and advice on chemistry for improvement of the initial hits via structure-activity relationship (SAR) and other medicinal chemistry approaches.  Overall, the MLPCN centers will provide needed assistance to assay submitters who are committed to preparing an adequate screening plan and grant application for the identification of small molecule probes.

How to apply for access to technical assistance of the MLPCN

Requests should be submitted at http://mli.nih.gov/mli/tech-assistance-request-form

In the online request form, you will be asked to provide the following information: 

1) Your contact information including your name, position and title, affiliated organization, email, and phone number. 
2) Assay target molecule(s), signaling pathway, or phenotype.
3) Potential scientific and/or therapeutic impact of the assay (please provide up to three literature references).
4) The availability and suitability (or lack thereof) of existing small molecule modulators.
5)  Preliminary low-throughput bench top assay data showing potential to be miniaturized for HTS.
6) Your secondary assays to rule out artifacts and to validate active compounds found in the primary assay as reproducible hits.

Notification of acceptance
You will be notified by email after your request is reviewed administratively by NIH staff.  We will process and respond to your request in a timely manner. 

Disclaimer
We may not be able to match all requests for technical assistance with a specific MLPCN center.

Inquiries

Inquiries should be directed to:

Yong Yao, Ph.D.
NIH Roadmap Molecular Libraries and Imaging
Division of Neuroscience and Basic Behavioral Science
National Institute of Mental Health
6001 Executive Boulevard, Room 7175, MSC 9641
Bethesda, MD 20892-964
Telephone: (301) 443-6102
Email: [email protected]