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Laboratory for Drug Discovery in Neurodegeneration

 

Collaborative ALS Drug Discovery Initiative (CADDI)

Based on a model pioneered by the Laboratory for Drug Discovery in Neurodegeneration, CADDI is a major new program of early stage ALS drug discovery projects that combine the biological and mechanistic expertise of investigators around the world with our dedicated drug discovery team.

We are pleased to announce the launch of a major new ALS drug discovery initiative within which we will engage investigators from around the world. For details, click here.

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The NeuroDiscovery Center's Laboratory for Drug Discovery in Neurodegeneration (LDDN) was established to discover chemical agents from which we and others will develop a new generation of drugs to treat neurodegenerative diseases (including degenerative diseases of the eye and ear). To accomplish this goal, LDDN has recruited a permanent staff of industry-seasoned scientists with expertise in assay development, laboratory automation, informatics, and medicinal chemistry, to work in close collaboration with principal investigators, post-doctoral fellows and graduate students from the neuroscience academic community. In this way, LDDN helps transform discoveries in the basic biology of neurodegeneration into opportunities for drug discovery.

Since becoming fully operational in 2002, the LDDN has established a track record of progress, including several projects that have progressed to testing candidate drugs in animal models of disease. In addition, the Harvard NeuroDiscovery Center has established several sponsored research agreements with biotechnology companies — two projects are of interest to a major pharmaceutical company and another was the foundation for a start-up biotechnology company. Finally, in 2005 the LDDN was awarded a substantial grant from the National Institutes of Health to create a National Center for Drug Discovery in Neurodegeneration (NCDDN). Each year the NCDDN brings in five new drug discovery projects from across the country.

Click here to view the current list of ongoing projects.

Program Resources 

The LDDN is a state-of-the-art drug discovery facility with 3,000 sq.ft. of dedicated research space in Cambridge, MA. We provide the NeuroDiscovery community with not only the physical resources for drug discovery, but crucially, the intellectual and program management help defining the most promising lines of investigation.

The LDDN staff includes two groups of scientists: (1) Collaborating investigators (CI) who are post doctoral scientists selected to work with the LDDN to transform basic neurobiological ideas into drug discovery programs and (2) permanent employees who work with the CIs to facilitate their projects. The latter group comprises three closely interacting areas: Leads Discovery, Medicinal Chemistry, and Informatics. These functions are staffed by experienced professionals with research and management experience in the biotechnology and pharmaceutical industries.

Assay Design and Development

The LDDN currently runs three types of assays: cell-based; protein polymerization; and enzyme activity. In general, our goal is the development of high-precision, homogenous assays that require as few additions and manipulations as possible. The development of these assays requires that visiting CIs work hand in hand with members of the Leads Discovery staff.

High-Throughput Screening

Screening is done via a robotic workstation. Assays are assembled on 384 well plates, test compounds are added and the completed assay mixtures are loaded into an automated multimodal plate reader where the readout is quantified. Data, which is collected locally by a PC interfaced to the plate reader, is then downloaded to a Sun server for processing and storage (see below). With our current robot system, we can screen a typical assay against 150,000 compounds in four to six weeks. "Hits" that are discovered in a screen are then confirmed and IC50 values determined. Assay hits that have well-behaved titration curves and IC50 values less than10 µM are then subjected to a series of secondary assays including validation assays, selectivity tests and mechanistic studies. In the selectivity assays, we determine how a given hit behaves in assays of targets that are similar to the primary assay. The goal is typically to focus on the most selective inhibitors. In mechanistic studies, we hope to discover how the compound interacts with its target.  

Medicinal Chemistry

Potent, selective, and mechanistically appealing compounds are optimized using an approach commonly referred to as medicinal chemistry. At this stage, optimization focuses on defining the structure-activity-relationship by testing analogs of the original structures for improving potency and selectivity. Later in the development of a series of compounds, optimization may focus on metabolic stability, solubility, bioavailability and toxicity.

Informatics

The data that drives all of these studies is handled by a sophisticated informatics system. The heart of our screening informatics are IDBS applications that are used for analysis and storage of chemical structures and biological assay data in Oracle database tables. Data flow begins with instruments recording screening results from 384-well plates in datafiles. These datafiles are imported into the IDBS Activity Base application. Data entered consists of percent inhibition or activation compared to a control. "Hits" are recorded as activity greater than 50% of the control. This threshold activity is selected so that the hit rate in the assay is < 0.5%. Each initial screen consists of over 150,000 compounds. Active compounds are re-assayed at three different concentrations and in triplicate. This second test confirms initial activity and measures dose-dependency. Chemical data is stored in Oracle tables by the IDBS application. The data consists of structures, registration numbers, molecular weights, calculated log-P (calculated octanol-water partition coefficients), and the number of hydrogen bond acceptors and donors. Biological data includes assay names and values. All data fields are searchable and can be queried in the Oracle database through the IDBS application. The IDBS Activity Base software provides a flexible means of defining templates for inputting and storing attributes of chemical and biological items and for reporting and querying. This provides a means for relating biological function to chemical structure and establishing correlations through data mining within one dataset and across multiple datasets.

Compound Screening Program

We encourage universities, for-profit, and non-profit institutions to work with us at the LDDN. We welcome research departments and others involved in the synthesis of "drug-like" molecules to submit compounds to the LDDN for testing in our various assays related to neurodegenerative diseases. We work to ensure that:

  • The interchange is procedurally simple and mutually beneficial.

  • Discoveries are shared jointly by the participating parties.

  • Access to all screening data for submitted compounds is provided to the participating party, upon request.

  • The submitted compounds are not shared with a third party without prior written consent. Interesting "hits" are pursued in a collaborative medicinal chemistry effort.

For information regarding compound submission, contact Greg Cuny, Director, Medicinal Chemistry at This e-mail address is being protected from spam bots, you need JavaScript enabled to view it or Tel 617.768-8640.

Access

LDDN's successful model of collaboration involves a collaborating investigator (CI) from laboratories within and beyond the Harvard Medical community to work with LDDN to: (1) design an assay based on the basic science the CI brings to the LDDN (2) develop this assay specifically for the purposes of high-throughput screening (HTS), (3) conduct a full-scale screen of LDDN's collection of more than 150,000 drug-like molecules; and (4) if screening results are sufficiently promising, work with LDDN medicinal chemists to optimize the compounds for greater potency. Typically the CI is a post-doctoral student or fellow who is able to dedicate most or all of his/her time to the project.

There are three paths for initiating these projects:

  1. The Harvard NeuroDiscovery Center provides funding to help promote collaborations. Requests For Applications (RFAs) are distributed to the community and details are posted on this site. View past and present awardees.

  2. Projects are initiated outside of the annual RFA procedure by contacting Ross Stein, Director of the LDDN.

  3. Projects are selected via the NIH NCDDN grant annual RFA.