Drug discovery

I am interested in exploring innovative and useful chemical tools and small molecules as probes to study biology and as therapeutics for disease treatment. My laboratory has been particularly interested in exploring chemical tools to address the important biological questions. I am a well-established investigator with over 20 years research experience and more than 240 peer reviewed publications (H-index: 72) in the fields of organic and medicinal chemistry and chemical biology. The small molecule-based fluorescence probes developed from my laboratory have been widely used by biomedical researchers as tools to study the cellular and molecular mechanisms. One of the small molecules discovered by my laboratory has been licensed to the Andaman Therapeutics for clinical trials as a new class of anticancer therapy.

Dr. Gerald (‘Gerry’) Maggiora, PhD, received a Bachelor of Science in chemistry and a PhD in biophysics from the University of California, Davis. He has more than 20 years experience in academia as a professor of chemistry and biochemistry at the University of Kansas, as well as five years as a professor in the College of Pharmacy at the University of Arizona. He has a comparable amount of experience in the pharmaceutical industry, where he served as the Director of Computer-Aided Drug Discovery for three different companies. His early work spanned numerous fields related to the development of quantum mechanical and molecular mechanics methods and their application to problems of mechanistic organic chemistry, vision, photosynthetic energy conversion, and the structural chemistry of drugs, biomolecules, and proteins. After joining the pharma industry, he directed his efforts towards the development and application of similarity and diversity methods and the analysis of biologically relevant chemical space to drug research. His recent work expands the concept of chemical space to include activity landscapes, which extend chemical spaces by including data on the activity of compounds in these spaces. This led to the notion of activity cliffs, which arise when two similar compounds exhibit significantly different activities, a phenomenon that runs counter to the well-known ‘Similarity-Property Principle’ that similar compounds tend to exhibit similar properties. Although relatively rare, activity cliffs provide significant information on structure-activity relationships that lie at the heart of drug design. He has also developed network-based representations of chemical space that circumvent many of the issues associated with the representation of these very high-dimensional spaces. He is currently continuing his work in this area. In recognition of his work in chemical informatics he received 2008 Herman Skolnik Award in Chemical Informatics presented by the Division of Chemical Information of the American Chemical Society.

Josef Vagner, PhD, is an Associate Research Professor at the University of BIO5 Research Institute and the Director of the Ligand Discovery Laboratory. Dr. Vagner is expert in the field of drug discovery and development, and he is focused on the design, synthesis, purification, characterization and screening of compound arrays.He has published over 70 original research papers and 31 patents. He is a frequent presenter at national and international meetings (American Chemical Society and Peptide Societies).Dr. Vagner designed and developed of compounds for in vivo pharmacologic applications and translation programs. He has over 25 years experience in synthesis and structural analysis of de novo ligands for various biological targets, including a recent focus on ligands targeting GPCRs and multivalent ligands. These experiences include 10 years of work in the pharmaceutical industry (Sanofi/ Selectide, Novo Nordisk, Discovery Partner International) where he specialized in combinatorial chemistry and array synthesis of small molecules. During his time in industry, he supervised teams of workers who successfully accomplished the synthesis of more than ten large libraries (with >10,000 compounds each).

Katrina Miranda, PhD, claims nitric oxide (NO), which is synthesized in the body via enzymatic oxidation of L-arginine, is critical to numerous physiological functions, but also can contribute to the severity of diseases such as cancer or pathophysiological conditions such as stroke. This diversity in the responses to NO biosynthesis is a reflection of the diverse chemistry of NO. For instance, NO can alter the function of enzymes by binding to metal centers. This type of interaction could result in outcomes as disparate as control of blood pressure or death of an invading bacterium. NO can also be readily converted to higher nitrogen oxides such as N2O3 or ONOOH, which have very different chemical and biological properties. The ultimate result will depend upon numerous factors, particularly the location and concentration of NO produced. Therefore, site-specific modulation of NO concentration offers intriguing therapeutic possibilities for an ever expanding list of diseases, including cancer, heart failure and stroke. As a whole, Dr. Miranda is interested in elucidating the fundamental molecular redox chemistry of NO and in developing compounds to deliver or scavenge NO and other nitrogen oxides. These projects are designed to answer questions of potential medical importance through a multi-disciplinary approach, including analytical, synthetic, inorganic and biochemical techniques.The project categories include five major disciplines. First, she will work on the development and utilization of analytical techniques for detection and measurement of NO and other nitrogen oxides as well as the resultant chemistry of these species. Second, she will synthesize potential donors or scavengers of NO and other nitrogen oxides. Third, it’s necessary to describe chemical characterization of these compounds (spectroscopic features, kinetics, mechanisms and profiles of nitrogen oxide release, etc.). Fourth, Dr. Miranda will try to describe the biological characterization of these compounds (assay of effects on biological compounds, mechanisms and pathways, in vitro determination of potential for therapeutic utility, etc.). Fifth, she will identify of potential targets, such as enzymes, for treatment of disease through exposure to nitrogen oxide donors. Keywords: cancer treatment, pain treatment

Christopher Hulme, PhD, focuses on small molecule drug design and developing enabling chemical methodologies to expedite the drug discovery process. Target families of particular current interest for the group are kinases, protein-protein interactions and emerging DNA receptors for indications in oncology. Such efforts are highly collaborative in nature and students will be exposed to the full array of design hurdles involved in progressing molecules along the value chain to clinical evaluation. These efforts will be aided by the group’s interest in both microwave assisted organic synthesis (MAOS) and flow chemistry. Both technologies enable ‘High-throughput Medicinal Chemistry’ (HTMC) and will be supported by similar High-throughput Purification capabilities.The group also has a long standing interest in the development of new reactions that produce biologically relevant molecules in an efficient manner. Front loading screening collections with molecules possessing high ‘iterative efficiency potential’ is critical for expediting the drug discovery process. The discovery of such tools that perturb cellular systems is of high value to the scientific community and may be facilitated by rapid forays into MCR space that can produce a multitude of novel scaffolds with appropriate decoration for evaluation with a variety of different screening paradigms.Novel hypervalent iodine mediated C-H activation methodologies is also an active area of interest. Probing the scope of the transformation below and investigating applications toward the synthesis of new peptidomimetics will be an additional pursuit in the Hulme group.

Despite many therapeutic successes, cancer remains a major cause of mortality in the US. Natural products (NPs) represent the best source and inspiration for the discovery of drugs and molecular targets. Our aim is to discover effective and non-toxic NP-based anticancer drugs. Working with NCI we have recently discovered a class of plant-derived NPs useful in cancer immunotherapy. The main focus of our current research is to utilize medicinal chemistry approach to obtain their analogues for preclinical evaluation. Leslie Gunatilaka is Professor at the School of Natural Resources and the Environment and Director of the Natural Products Center. He is also Adjunct Professor of Department of Nutritional Sciences, and a member of the Arizona Cancer Center. He is a member of several professional societies, editorial boards, and pharmaceutical company advisory groups. He is a Fellow of the Academy of Sciences for the Developing World (TWAS), Italy, and the National Academy of Sciences, Sri Lanka. Dr. Gunatilaka has over 200 peer-reviewed publications and book chapters and over 150 communications in natural product science to his credit. He is the recipient of the Sri Lankan Presidents’ gold medal for “creating a center of excellence in natural products research at the University of Peradeniya, Sri Lanka” (1987), CaPCURE award for “dedication to ending prostate cancer as a risk for all men and their families” (2000), Research Faculty of the Year Award of the UA College of Agriculture and Life Sciences (2003), the UA Asian American Faculty, Staff and Alumni Association Outstanding Faculty Award (2005), and the UA Leading Edge Researcher Award for Innovative Research (2012). He has delivered over 100 invited lectures worldwide and was the Chief Guest and Plenary Lecturer at the International Herbal Medicine Conference held in Sri Lanka (2005), and the Keynote Speaker and the Guest of Honor at Chemtech-2007, an International Conference organized by the Institute of Chemistry, Ceylon. His current research interests include discovery, identification of protein targets, and structure-activity relationship (SAR) studies of natural product-based drugs to treat cancer, neurodegenerative, and other diseases from plants, and plant- and lichen-associated microorganisms, maximization of chemistry diversity and production of microbial and plant secondary metabolites, and scientific investigation of medicinal plants and herbal supplements. Keywords: Natural Product-Based Drug Discovery, Medicinal Chemistry, Cancer Immunotherapeutic Agents

I am a senior research scientist and oversees medicinal chemistry research at BIO5 Institute's drug discovery initiative. I oversee group of medicinal chemistry involved in the development of small molecule therapeutics for idiopathic pulmonary fibrosis (IPF), neuropathic pain, acute lung injury and cancer. I am co-founder of Reglagene and Regulonix - two biotech companies with startup technology from the University of Arizona. I have 15 years' experience in medicinal chemistry with expertise in translational drug development. I am also a co-inventor of small molecules targeting hTERT and MYC for the treatment of glioblastoma, melanoma, lymphomas and prostate cancer. Our work in the area of neuropathic pain has led to successful funding from Tech Launch Arizona and will result in STTR funding from NIH.

Dr. Minying Cai is currently a research professor in the Department of Chemistry and Biochemistry at the University of Arizona. She has been working in the Chemistry & Biochemistry department for more than 16 years and has more than 100 publications in the area of novel drug discovery for obesity, diabetes, cancer and pain. Dr. Cai received the Ph.D. at the University of Arizona in Biochemistry and Molecular Biophysics in 2004. Before that, she had been working in Shanghai Institute of Materia Medica; Shanghai Research Center of Biotechnology in Chinese Academy of Sciences. Dr. Cai has been working on peptide based drug discovery for more than 23 years, starting with discovery of developing anti-microbial peptide and insulin related peptide drug. Sixteen years ago, she started working on melanotropin and opioid related drug discovery. Dr. Cai's research in peptides involves highly multidisciplinary areas including chemistry and biochemistry; molecular pharmacology, molecular imaging, and cancer research, with expertise in molecular pharmacology, synthetic, organic and peptide methodology, chemical and biophysical analysis and evaluation, and in vitro and in vivo expression. Dr. Cai is currently working on several projects at the interface of chemistry, pharmacology and biology within the areas of: 1. Structure based drug design and synthesis of GPCR ligands, including developing selective hMCRs ligand; 2. Developing novel biophysics tools for molecular imaging; novel biomarker for high-throughput screening system. 3. Exploiting novel scaffold via computational chemistry for small molecule therapeutics for energy balance and cancer study; 4. Creating a nanostructured integrated platform for biodetection and imaging-guided therapy. Keywords: Drug Discovery, Melanoma Prevention, neurodegenerative diseases, Obesity and Diabetes, Melanocortin System

Dean Billheimer, PhD, works with the Arizona Statistics Consulting Laboratory (StatLab) to partner with scientists and physicians to advance discovery and understanding. The 'Stat Lab' provides statistical expertise, personnel and computing resources to facilitate study design and conduct, data acquisition protocols, data analysis, and the preparation of grants and manuscripts. Dr. Billheimer also works to adapt and develop new statistical methods to address emerging problems in science and medicine. Dr. Billheimer facilitates discovery translation and economic development by consulting with public and private organizations external to the University of Arizona. Keywords: Biostatistics, Bioinformatics, Study Design, Bayesian Analysis