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Dr. William J. (Bill) Welsh holds the Norman H. Edelman Endowed Professorship in Bioinformatics and Computer-Aided Molecular Design in the Department of Pharmacology at the Robert Wood Johnson Medical School (RWJMS) in Piscataway NJ, University of Medicine and Dentistry of New Jersey (UMDNJ). Concurrently, he serves as Director of the UMDNJ Informatics Institute (http://informatics.umdnj.edu) that coordinates University-wide initiatives in bioinformatics, chemical informatics, and computer-aided molecular design. He is also PI and Director of the EPA-supported New Jersey Research Center for Environmental Bioinformatics and Computational Predictive Toxicology (ebCTC: http://www.ebCTC.org) the first of its kind in the nation. He is a member of various centers and institutes of excellence at UMDNJ and Rutgers University, including the Cancer Institute of New Jersey, the New Jersey Center for Biomaterials, Rutgers University School of Pharmacy, and the Environmental & Occupational Health Sciences Institute (EOHSI).
Dr. Welsh earned a B.S. degree (magna cum laude) in Chemistry from St. Joseph’s University (Phila., PA) in 1969 and a Ph.D. degree in Theoretical Physical Chemistry in 1974 from the University of Pennsylvania (Phila., PA). He was employed as a research scientist at the Procter & Gamble Company (Cincinnati, OH) from 1975 until 1980, then pursued postdoctoral training in the laboratory of Prof. James E. Mark, Distinguished Professor of Polymer Science at the University of Cincinnati (Cinti., OH). In 1985, Dr. Welsh joined the University of Missouri (St. Louis) as an Associate Professor of Chemistry and rose through the ranks to Distinguished Professor in 1998. During this period he was appointed Director, Laboratory for Computer-Aided Molecular Design, at the University of Missouri. In 2001, Dr. Welsh joined UMDNJ-Robert Wood Johnson Medical School to assume his present role.
Dr. Welsh’s laboratory specializes in the development and application of computational tools for pharmaceutical drug discovery. Promising bioactive molecules emanating from these computational approaches are synthesized and tested as potential therapeutic or diagnostic agents. His laboratory is widely reputed for its innovation, such as the development of the Shape Signatures tool and the discovery of potential drug candidates for the treatment cancer, severe and chronic pain, and infectious diseases. Dr. Welsh’s publication record includes over 300 articles in peer-reviewed books and journals, 600 abstracts from presentations at professional scientific meetings, and several patents and patent applications. He is the recipient of numerous awards and honors, including the Teacher of the Year Award (1983 and 1985), the St. Louis Research Award (1998), the University of Missouri-St. Louis Chancellor’s Research and Creativity Award (2001), the University of Missouri Entrepreneur of the Year Award (2001), the Norman H. Edelman Endowed Professorship in Bioinformatics at UMDNJ-RWJMS (2003), and most recently the John C. Krantz, Jr. Award (2004). He serves on the advisory boards of several scientific journals. Spanning the last twenty years, over 200 students (postgraduate and graduate students, undergraduates, and research associates) have trained in his laboratory. His current research group includes 6 graduate students and 9 postgraduate students. In October 2006, Dr. Welsh launched the start-up company Snowdon, Inc., (www.snowdonpharma.com) based on technology licensed from his academic laboratory at UMDNJ.
Summary of Research Activities
Drug Discovery, Computer-Aided Molecular Modeling and Design, Bioinformatics and Cheminformatics
Our laboratory specializes in the development and application of computational tools in bioinformatics, cheminformatics, and computer-aided drug discovery. Examples of active research projects are described below.
- Novel Opioid Receptor Active Agents
Our laboratory has discovered a new class of small-molecule compounds, structurally distinct from morphine-like opiates, that exhibit strong binding affinity (low nanomolar range) and selectivity for the opioid receptors. Potential therapeutic applications include analgesics, immunomodulatory agents, and treatments for narcotic addiction.
- Tubulin Polymerization Inhibitors as Anti-Cancer Therapeutic Agents
We have designed, synthesized, and tested a novel series of small-molecule tubulin-binding compounds as potential anti-cancer therapeutic agents. Our lead compounds, which exhibit strong cytotoxic activity (low nanomolar range) against a broad array of cancer cell lines including multi-drug resistant (MDR) cells, are currently undergoing extensive in-vivo evaluation using animal models.
Evidence reveals that ACK kinase plays a key role in the survival of v-Ha-Ras-transformed cells suggesting that ACK may be a good target for developing a therapy for Ras-induced cancer. Based on the recently published x-ray crystal structure of ACK, we are collaborating in the structure-based design and biological testing of small-molecule ACK inhibitors.
- Phytoestrogens for Chemoprevention and Treatment
Clinical evidence suggests that estrogenic compounds, or herbal products containing phytoestrogens, have clear activity in early-stage and advanced prostate cancer. In collaboration with scientists at the Cancer Institute of New Jersey, we are employing bioinformatics and computer-aided molecular modeling tools to understand the effect of estrogenic products and support the rational design of chemopreventive estrogens.
- Na,K-ATPase Inhibitors for Treatment of Cardiovascular Diseases
Our laboratory has constructed a structural model for human Sodium Potassium (Na, K-) ATPase, the target for cardioglycosides such as digoxin and digitoxin which are “first line” treatments for congestive heart failure and related conditions. Unfortunately, these two cardioglycosides have narrow therapeutic indices resulting in severe toxic side effects. Based on our structural model, we have elucidated the putative mechanism of action of these cardioglycosides to guide the rational design of a new generation of effective yet safer therapeutic agents.
- Nuclear Hormone Receptors
The nuclear receptors, such as the estrogen receptor (ER) and androgen receptor (AR), are hormone-dependent transcription factors that control many reproductive, developmental, and metabolic functions in humans and wildlife. Our laboratory has developed computer-based molecular models to guide the discovery of novel therapeutic agents for the treatment of pathologies such as breast cancer and prostate cancer that are mediated through nuclear receptors. Another focus of study is the steroid & xenobiotic receptor (SXR/PXR), a nuclear receptor that has been implicated in metabolic pathways, adverse drug-drug interactions, and multi-drug resistance (MDR).
Novel molecules have been discovered that inhibit the motility and invasion machinery of Apicomplexan parasites associated with serious diseases, including malaria, toxoplasmosis and cryptosporidiosis.
We have co-developed a novel computational tool for drug discovery known as “Shape Signatures” that rapidly matches small drug–like molecules against each other based on similarity in shape and electrostatic properties.
- Novel Strategy for Therapeutic Treatment of Amyloid Diseases
Amyloid fibril formation is associated with many lethal diseases including Alzheimer’s disease, Parkinson’s disease, and Type II diabetes. Our laboratory has developed a computational tool that identifies those sequences within proteins or polypeptides which are especially susceptible to amyloid fibril formation. We call this susceptibility “hidden -strand propensity”, since it refers to the strong propensity for specific sequences to transform from their native helical or coil secondary structure to -strands under certain physiologically relevant conditions. We are now applying this predictive tool to guide the discovery of novel therapeutic agents useful for the prevention and treatment of amyloid diseases.
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