Academic Access Program Members

Dr. Tomas Mustelin
The Burnham Institute, San Diego California

In Dr. Mustelin's group we investigate a family of genes called protein tyrosine phosphatase (PTPases), many of which act as tumor suppressors in numerous types of human cancer. It is anticipated that damage or loss of many additional family members will be found to underlay human disease, particularly cancers of white blood cells (e.g. leukemios and lymphomas). Dr. Mustelin has generated the tools to study some 35 different PTPases, representing nearly half of the all genes in this family in the human genome. Dr. Mustelin's work aims at understanding the exact function of each of these PTPases in the cell's machinery for growth, survival, and death, in the white blood cell system. The results of Dr. Mustelin's research will help him and others to design rational approaches for the combat of cancer and other diseases.

Laboratory of Dr. John C. Reed, President and CEO
The Burnham Institute, San Diego California

In Dr. Reed's lab, we are doing research on basic regulatory mechanisms of apoptosis, and try to apply how those mechanisms go awry in disease states. Some of the discoveries made by the laboratory include (a) study of the role of Bcl-2 in cancer, and use of anti-sense methods to reduce Bcl-2 expression to make tumor cells sensitive to anti-cancer drugs (b) research about the critical role of mitochondria in apoptosis mechanisms; (c) discovery that p53 induces transcription of death-gene Bax, representing the first p53–inducible pro-apoptotic gene; (d) discovery of the mechanism of IAP-family proteins; (e) study of BAG-Bcl2 family proteins and their role in resistance to cell stress; and (f) development of biomarkers that predict clinical phenotype in cancer patients.

Dr. Brent Stockwell group
Columbia University, Dept. Biological Sciences, New York, NY

Dr. Stockwell's laboratory uses small molecule tools to probe the signaling networks underlying cell death, particularly as it relates to neurodegeneration and cancer. Using cell-based, high-throughput assays, this interdisciplinary team of researchers identifies small molecules that suppress or enhance cell death in the presence of specific mutant alleles. The compounds are subsequently used to create affinity reagents that reveal novel proteins involved in regulating cell death phenotypes.

John Whitlow and Professor Yumin Li
East Carolina University

John Whitlow an undergraduate chemistry student under the supervision of Chemistry Professor Dr. Yumin Li, is employing ChemNavigator's iResearch Library and 3DPL Searcher as part of a research project to find molecules with an affinity for the active binding site of S100B that is implicated in disrupting p53 function. The iResearch Library database will be docked into the pre-calculated binding pocket of S100B. Additional plans include performing follow up studies to test candidate molecules generated in this study for ADME properties, synthesizability, and energy simulations using Amber.

Dr. Igor V. Tetko, Institute for Bioinformatics
GSF - National Research Centre for Environment and Health

Dr. Tetko is performing research on how to share information about molecules without revealing their detailed structures (i.e., if it is possible to develop a secure system to transmit indices that can be used to model molecular properties but not to recover their structures). He and his colleagues also access the accuracy of prediction and applicability domain of ADMET models and methods to predict physio-chemical properties of compounds in the early stages of drug development. The iResearch Library unique structure table offers an excellent source for structural analysis of million of unique chemical structures in this research program.

Laboratory for Drug Discovery in Neurodegeneration
Harvard NeuroDiscovery Center

The HCNR 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 Alzheimer's disease, ALS, Huntington's disease, MS, Parkinson's disease, and other neurodegenerative diseases (including degenerative diseases of the eye and ear).

ICCB - Longwood Screening Facility - Harvard Medical School
The ICCB-Longwood Investigator Initiated Screening Program assists academic researchers in carrying out high-throughput screens of chemical libraries to identify new tools for biological research. The ICCB-Longwood screening facility is built around modular work stations, and assays are generally carried out in 384-well plates. The ICCB-Longwood compound collection is continuously growing, and over 150,000 compounds are currently available for screening. The facility employs a staff-assisted screening model, in which investigators using the facility are provided with access to compound libraries and training in the use of some instruments, such as liquid handling equipment, plate readers, and screening microscopes. Staff members run all complex automation for screens.

The ICCB-Longwood screening effort is expanded through close interactions with two other Harvard Medical School-affiliated programs, the National Screening Laboratory for the Regional Centers of Excellence in Biodefense and Emerging Infectious Disease (NSRB) and the Laboratory for Drug Discovery (LDDN). Together, these three screening efforts focus on broadly different areas, but all share the goal of using small molecule screens to analyze a variety of biological processes. Compound libraries and other resources are shared among the three groups, with each providing support in its particular area of expertise.

Dr. Salimuddin Shah
Macromolecular Analysis Shared Resource, Lombardi Comprehensive Cancer Center at Georgetown University

Lombardi Comprehensive Cancer Center is the NCI-designated Comprehensive Cancer Center located in the Washington, DC area. The Lombardi Comprehensive Cancer Center (LCCC), part of Georgetown University Medical Center and Georgetown University Hospital, seeks to improve the diagnosis, treatment, and prevention of cancer through innovative basic and clinical research, patient care, community education and outreach, and the training of cancer specialists of the future. Lombardi's internationally-renowned clinical team offers the latest treatments for virtually every type of cancer, with a particular emphasis in solid tumors and adult and pediatric hematologic cancers. LCCC maintains various shared resources to provide centralized facilities for the LCCC investigators. As part of the LCCC research programs, the MASR provides services in molecular modeling and other related areas.

Specifically, MASR provides service for microarray analysis, DNA sequencing, computer aided drug discovery and protein modeling. For molecular modeling support MASR have several workstations and softwares. The systems are used for the purpose of computer aided drug discovery, protein modeling, and studying macromolecular structures at the atomic level as well as interactions between molecules. Computational and biological researchers at the LCCC will use the iResearch Library database of structures representing commercially available compounds both as input for computational models and as a means to identify sources for additional chemical samples.

The National Screening Laboratory for the Regional Centers of Excellence in Biodefense and Emerging Infectious Diseases (NSRB)
New England Regional Center of Excellence (NERCE), Harvard Medical School

The NSRB supports research directed towards the identification of small molecules that enhance our understanding of the basic biology of pathogens relevant to biodefense or emerging infectious disease, and development of new therapeutic agents against these NIAID Priority Pathogens. The NSRB provides access to small molecule collections and assistance in conducting and interpreting high-throughput screens for all investigators conducting research relevant to these aims. The NSRB also has medicinal chemistry capability to advance promising screening hits toward pharmaceutical development.

The NSRB is administered by the New England Regional Center of Excellence for Biodefense and Emerging Infectious Diseases (NERCE/BEID) and interacts closely with the Institute for Chemistry and Cell Biology (ICCB) and the Laboratory for Drug Discovery in Neurodegeneration (LDDN). These three entities focus on broadly different areas, but all share the goal of using small molecule screens to analyze biological processes. The NSRB and LDDN target the biology of certain disease areas and specifically plan to identify and develop new therapeutic leads. Compound libraries and other resources are shared among the three groups, with each providing support in its particular area of expertise. Scientific direction and project prioritization is the responsibility of the NSRB Advisory Committee, which includes representatives from all eight RCE centers.

Dr. Peter Howley Group
Pathology Department, Harvard Medical School

Human papillomavirus (HPV) is the causative agent of cervical cancer. We are performing chemical genetic analysis to identify small molecule inhibitors of the p53 degradation pathway mediated by HPV E6 oncoprotein. Inhibition of this pathway may induce cell death of cervical cancer cells.

Dr. Martin Herbst, Neuroproteomics group
Max-Delbrück-Centre for Molecular Medicine, Berlin, Germany

The main objective of the group's work is to understand the pathomechanisms of late onset neurodegenerative disorders such as Huntington's, Parkinson's, Alzheimer's and Machado Joseph disease and to develop causal therapies for them. The research group is concerned with the identification of chemical compounds that inhibit aggregate formation in in vitro model systems.

Yuk-Ching Tse-Dinh, Professor
New York Medical College, Dept. of Biochemistry & Molecular Biology, Valhalla, NY

DNA topoisomerases are ubiquitous enzymes involved in DNA replication, transcription and recombination. Small molecules targeting type IA DNA topoisomerases have not been discovered. A high-through-put assay is being carried out by the Primary Investigator at the NSRB facility at Harvard Medical School to screen the 150,000 compounds available for small molecules that will result in accumulation of covalent complex formed by recombinant Yersinia pestis topoisomerase I. Hits will be characterized at New York Medical College with in vitro topoisomerase enzyme assays and bacterial cell killing. The selected initial hits will be further developed in collaboration with medicinal chemists at NSRB. Analogs to initial hits will be identified for SAR analysis. Genetic studies will be carried out to confirm the in vivo target of the compounds found to inhibit bacterial topoisomerase I in vitro.

Dr. Lakshmipathi Pandarinathan
Chemistry Department, Center for Drug Discovery, Northeastern University

The Endocannabinoid System in Drug Discovery: Cannabinergic drugs modulate the central nervous and immune systems by acting through two receptors (CB1; CB2) and two classes of endogenous ligands represented by anandamide and 2-arachidonyl glycerol (endocannabinoids). The endocannabinoid system is further regulated by the inactivating enzyme, fatty acid amide hydrolase (FAAH), and a newly discovered transport system. We are studying the interactions of cannabinergic ligands with the above receptors, enzymes and transporters using a combination of chemical, biochemical, biophysical and computational methods. Our results are further used to design and synthesize novel therapeutically useful drugs for pain, appetite and central nervous system diseases.

Interactions of Drugs with Membranes: We study the effects of drug molecules on membranes using solution and solid-state nuclear magnetic resonance and computational methods and use the results are used to design and synthesize improved medications. The classes of drugs being studied include cannabinoids, steroids and antineoplastic ether lipids. The work also includes studying the mechanism by which these molecules are transported across the blood brain barrier.

Dr. Jodi Nunnari, Molecular & Cellular Biology
University of California at Davis, Department of Biological Sciences

Research in the Nunnari laboratory is devoted to understanding how the behavior of mitochondria is controlled in cells. Specifically, we are focused on two fundamental problems. The first is how the structure of mitochondria is established and maintained within cells. We are currently elucidating the molecular mechanisms that underlie mitochondrial division and fusion. Our second area of interest is understanding how the mitochondrial genome is organized and faithfully segregated within the organelle. The inheritance of mitochondria and mitochondrial DNA (mtDNA) is influenced by the morphology of the organelle and by specific mtDNA-associated structures: proper inheritance is essential for cell survival and for respiratory competence. In addition, the regulation of mitochondrial copy number, morphology and distribution is critical for normal cellular differentiation and function. Not surprisingly, defects in mitochondrial structure and mtDNA maintenance are associated with an increasing number of human diseases.

Dr. Piomelli
University of California, Irvine, Department of Psychiatry

Research in Dr. Piomelli's lab at University of California, Irvine dept. of Psychiatry, is focused on the function of lipid-derived messengers, with particular emphasis on the endogenous cannabinoids anandamide and 2-arachidonylglycerol. Current research efforts converge on three areas: formation and inactivation of anandamide and 2-arachidonylglycerol; physiological roles of the endogenous cannabinoid system; development of therapeutic agents that target anandamide and 2-arachidonylglycerol metabolism. In Chemnavigator's library we will be searching for a compound which can inhibit the hydrolysis of these endocannabinoids.

Dr. Michael K. Gilson group
University of Maryland Biotechnology Institute, Center for Advanced Research in Biotechnology, Rockville, MD
The research program for which the lab will use ChemNavigator is one that aims to develop and apply a method of designing HIV protease inhibitors that will work against wild-type and mutant variants of the enzyme.

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