Medicinal Chemistry

Medicinal Chemistry at Southern Research has a strong record of achievement, including the synthesis and discovery of more than 20 compounds that have entered clinical trials and seven drugs with FDA approval. Our staff currently focuses on three primary therapeutic areas: cancer, infectious diseases, and CNS/neurological diseases.

Our chemists have experience and expertise in utilizing modern discovery techniques including:

• Molecular Modeling and Computer-Assisted Drug Design
• Structural Biology and X-Ray Crystallography
• Synthetic Organic Chemistry and Parallel Synthesis
• Structure-Activity Relationships
• Process Scale-Up
• Repository and Database Services

In addition, our scientists have access to a proprietary internal compound repository for the initial discovery of compounds with activity against new biological targets. We also undertake custom synthesis projects and actively seek collaborative licensing opportunities for our unique in-house chemical repository.

Capabilities

A few of the broad capabilities provided by Southern Research medicinal chemists include:

• Use of computational methods/strategies such as homology modeling, structural and property analysis, conformational sampling, pharmacophore modeling, structure-activity relationship analysis, ligand docking, scoring, virtual screening and data mining methods (Hobrath)
• Computational studies on protein structure prediction, protein-protein interactions, and protein-ligand interactions including virtual screening to explore underlying mechanisms relating protein structure, dynamics and functions, including GPCRs, protein kinases, and neurotransporters (Zhang)
• Parallel synthesis and library design based on sugar, purine, oxazoline, pyridooxazole, pyridopyrimidine, and natural product (fumagillin) scaffolds with solid-, solution-, and liquid-phase methodologies employing both robotic and manual protocols (Maddry, Pathak)
• Ionic, liquid-supported, solution-phase methodology for synthesis of biologically relevant oligosaccharides (Pathak)
• Small molecule analytical and spectroscopic characterization using the following equipment: (Riordan)
• Nuclear magnetic resonance (NMR) spectroscopy
• 2 400-MHz NMR spectrometers 600- and 500-MHz NMR spectrometers at UAB's Comprehensive Cancer Center
• Fourier transform infrared (FTIR) spectroscopy
• Ultraviolet (U.V.) spectroscopy
• Mass spectrometry
• Carbon hydrogen and nitrogen (CHN) elemental analysis
• High performance liquid chromatography (HPLC)

Projects

Examples of specific research projects being conducted by our medicinal chemists are:

• Development and synthesis of nucleoside analogs as potential antiviral and anti-infective agents (Kwong)
• Design and synthesis of potential drug candidates targeted toward enzymes, membrane bound receptors (GPCRs), ion channels and neurotransmitter transporters of the central nervous system (CNS) (Ananthan)
• Design, synthesis and development of opioid ligands as novel analgesic agents (Ananthan)
• Novel ligands possessing selective interaction profiles with the biogenic amine transporters (dopamine, norepinephrine and 5-hydroxytryptamine) for discovering compounds with the potential for therapeutic application in several CNS disorders including addiction (Ananthan)
• Structural biology and molecular mechanisms of key enzymes in the nucleoside metabolic pathway in Mycobacterium tuberculosis. Use of crystals of adenosine kinase and X-ray diffraction data for determination of high resolution structure (Li)
• Studies of enzymes in the folate biosynthesis/metabolic pathway in M. tuberculosis, Francisella tularensis, and Bacillus anthracis (Li)
• Studies of structure and function of protein kinases and other signaling molecules implicated in cancer (Li)
• Carbohydrate chemistry (Pathak)
• Anti-mycobacterium drug design, drug delivery, and new synthetic procedures to obtain oligosaccharides (Pathak)
• Semi-synthesis of bioactive natural products, such as new semi-synthetic triterpene saponin as a vaccine adjuvant/immune stimulant (Pathak)
• Design and synthesis of small-molecule inhibitors against key enzymes such as fatty-acid biosynthesis and glutamate racemase in Mycobacterium tuberculosis and Francisella tularensis (Pathak)
• Anti-mycobacterial drug design (Reynolds)
• Novel antisense oligonucleotides for the treatment of cancer and viral infections (Reynolds)
• New dihydrofolate reductase inhibitors to treat bacterial diseases and cancer (Reynolds)
• Design and preparation of novel inhibitors of the bacterial tubulin homolog FtsZ (Reynolds)
• Discovery of novel inhibitors of the serine proteases implicated in cancer metastasis and the kinases driving neurodegenerative disease (Galemmo)