University of California, Riverside

MolMed



Infrastructure & Enabling Technologies


infrastructure

Infrastructure and Enabling Technologies

Investigators at the Center for Molecular and Translational Medicine use modern and innovative drug discovery technologies that may reveal therapeutic targets that previously have been considered “undruggable.”

Our investigators have a number of resources and infrastructures available at UC Riverside, as well as at nearby collaborating institutions including, UC San Diego, UC Los Angeles, Riverside Community Hospital, Desert Region Medical Center (Palm Springs, Calif.), City of Hope (Duarte, Calif.), Cedars-Sinai Medical Center (Los Angeles, Calif.), and Loma Linda University Health.

Rational Drug Design and Ligand Design Guided by Biophysical Methods

Fragment- and Structure-based Drug Discovery

Professor of Biomedical Sciences Maurizio Pellecchia of the School of Medicine uses a combination of high-field NMR spectroscopy, combinatorial chemistry (HTS by NMR), and fragment-as-structure-based drug design approaches to derive novel pharmacological tools targeting protein-protein interactions. Similar approaches have recently led to the FDA approval of the very first drug targeting a PPI, namely the Bcl-2 antagonist Venetoclax. The laboratory also utilizes advanced biophysical and biochemical approaches including isothermal titration calorimetry measurements to characterize the thermodynamics and kinetics of ligand binding. These approaches have enabled the design of 123C4, a novel potent and selective EphA4 ligand that is being developed for the treatment of ALS.

Along the same lines, Assistant Professor of Biochemistry Jefferson Perry, Assistant Professor of Biochemistry Jikui Song and Associate Professor of Biochemistry Li Fan of the UCR College of Natural and Agricultural Sciences use X-ray crystallography to solve the three-dimensional structure of relevant drug targets in complex with putative ligands. In addition, the laboratories utilize libraries of low molecular weight “fragments” and high-throughput X-ray studies to guide the identification and optimization of lead compounds. These strategies are similar to what has been very recently used to derive the first fragment-based derived inhibitor of a melanoma drug target, leading to the FDA approved agent Vemurafenib.

Bioinformatics, Computational Chemistry, Virtual Docking and Virtual Screening

Scientists at UCR take advantage of advanced computational chemistry approaches accelerate drug discovery and development. Professor of Bioengineering Dimitrios Morikis of the Bourns College of Engineering uses structure-dynamics-interactions-function relations, quasi-dynamic pharmacophore models, and high-throughput computational protocols to design low-molecular mass inhibitors. His laboratory has also developed a translational bioinformatics tool, based on a mathematical model that describes the dynamics of the complement system activation pathways. This tool has the potential for a clinical application in personalized treatment of patients with genetic predisposition for complement-mediated diseases.

Another translational bioinformatics tool for patient-specific drug treatment is based on a probabilistic model for co-receptor selectivity of HIV-1 entry in human cells. Other tools developed by Morikis’ lab involve structural bioinformatics computational frameworks for peptide and protein design, based on molecular dynamics simulations and electrostatic calculations, and pharmacophore-based virtual screening of chemical compounds.

Associate Professor of Chemistry Chia-en Chang develops and applies computational tools to predict and understand protein and drug binding affinities and kinetics. The Chang group uses rigorous free energy calculations to assist/guide structure-based drug design. In addition to how tight a compound can bind, how long a drug can stay and inhibit its target protein, so called residence time, also plays an important role related to in vivo efficacy. Therefore, the Chang group also investigates how ligands can bind and leave fast/slowly using new and existing computational tools that helps researchers design compounds with desired drug binding kinetics.

Pellecchia utilizes computational docking studies, when possible aided by NMR, mutagenesis, or X-ray data, to conduct virtual screening of combinatorial libraries and to guide hit-to-lead optimizations. In addition, the Bioinformatics Core Facility within the Institute for Integrative Genome Biology at UC Riverside provides a tremendous resource for scientists with dedicated hardware and over 500 open source bioinformatics software packages for NGS analysis, comparative genomics, data mining, statistics, molecular modeling, and cheminformatics.

Professor of Bioinformatics Thomas Girke of Botany and Plant Sciences in the College of Natural and Agricultural Sciences focuses on the development of computational data analysis methods for genome biology and small molecule discovery. This includes discovery-oriented data mining projects, as well as algorithm and software development projects for data types from a variety of high-throughput technologies such as next generation sequencing (NGS), genome-wide profiling approaches and drug discovery.

Combinatorial Chemistry

In drug discovery, even minor modifications to a hit compounds can result in dramatic changes in biological efficacy or pharmacokinetic or the agent, making the process of lead optimization daunting. Hence, novel methods that accelerate the synthesis of unique molecules are much needed to enable the rapid exploration of the chemical and biological space of a given compound series. Pellecchia utilizes fragment-based positional scanning approaches, combined with NMR spectroscopy for hit identification, to derive and test large libraries of compounds around a given initial hit or fragment. In addition, the strategy is amenable to the design and synthesis of peptide-mimetics to target PPIs.

Associate Professor of Chemistry Catherine Larsen of the College of Natural and Agricultural Sciences, developed innovative green syntheses in which commercially-available starting materials are converted into nitrogen-containing compounds ranging from heteroaromatics to tetrasubstituted alpha-amino carbon centers. As organometallic catalysts and organocatalysts often enable complementary transformations, both can be used to develop mechanistically distinct reactions that produce functionally diverse compounds with applications for the synthesis of pharmacologically active natural products and/or for the development of novel therapeutics. 

Distinguished Professor of Chemistry Michael Pirrung of the College of Natural and Agricultural Sciences is a pioneer the field of microarrays, which have important biological applications in genomics. He has developed innovative approaches in combinatorial chemistry, using solid-phase synthesis and natural products, and in biological assays using novel optical methods.

Nanotechnology & Diagnostics Applications

Engineering of Theranostics

Professor of Bioengineering Bahman Anvari’s laboratory in the Bourns College of Engineering focuses on the design and engineering of biologically-derived constructs as photo-activated theranostic agents for optical imaging and phototherapy of specific diseases. The lab has developed platforms derived from mammalian cells (erythrocytes) as well as genome-depleted plant-infecting viruses that can be doped with various near infrared organic chromophores with potential applications ranging from photo-treatment of cutaneous capillary malformations to cancer and vascular imaging.

Measurement of Small Circulating Oligonucleotides as Prognostic, Diagnostic or Treatment Indicators

Professor of Biomedical Sciences Ameae Walker of the UCR School of Medicine and colleagues have developed a simple, inexpensive and effective method for measuring small oligonucleotides in samples of plasma or serum. The small oligonucleotides may be prognostic or diagnostic microRNAs or administered oligonucleotide therapeutics. The method does not require PCR or any equipment beyond that present in an average clinical laboratory. A patent application has been filed.

Genomics, Proteomics, and High-Throughput Screening (HTS)

Keen Hall is a 10,000-square-foot instrumentation facility that offers expertise and instrumentation in microscopy/imaging, proteomics and genomics and chemical biology.

  • The Genomics Core Facility provides technical, instrument, and professional development and next generation sequencing, gene expression services, flow cytometry.
  • The Proteomics Core Facility has a series of instruments for protein separation, sample preparation, and mass spectrometry analyses.
  • The Microscopy and Imaging Core Facility provides a comprehensive suite of confocal microscopes and supporting peripheral equipment with high throughput imaging capability and a range of optical imaging applications.
  • The Chemical Screening Facilities feature diverse chemical libraries, robotics and cheminformatics that support the core facilities. Instruments include two BioTek Precision 2000 liquid-handling robots in laminar flow hoods for clean work and a Beckman Coulter Biomek FX double bridge fluid handling robot with Cytomat hotel, for library management and distribution.

    Compounds collections are available from commercial sources.
  • For follow up and SAR studies, the ChemMine Web Tools package  is an online service for analyzing and clustering small molecules by structural similarities, physicochemical properties or custom data types. Compounds structures can be imported into the workbench by simple copy/paste, local files or from a PubChem search.

Quantitative FRET Technology Platform for High-Throughput Screening and Drug Characterizations

A novel quantitative Förster resonance energy transfer (FRET) methodology has been developed using one-sample method for both basic kinetics parameter determinations and high-throughput screening (HTS) assays in Associate Professor of Bioengineering Jiayu Liao’ group at UCR's Bourns College of Engineering.

The FRET assay has been widely used in various biological research in vitro and in vivo. However, the quantitative FRET assay has not been fully established due to the complexity of FRET signal. We have developed a novel approach to determine the absolute FRET signal in a three-step procedure using cross-wavelength correlation coefficiency method and then correlate the absolute FRET signal with the molecular events of various biochemical reactions in SUMOylation cascade for their kinetic parameter determinations.

Ubiquitin-like protein pathways, such as SUMOylation, are critical in protein homeostasis and activities in vivo and are emerging as a novel strategy to treat many acute and chronic human diseases, such as anti-infections and cancers. The high-throughput screening (HTS) assay has also been developed and applied in a HTS campaign for more than 220,000 compounds and a specific SUMO inhibitor was discovered and characterized in both anti-influenza virus assay and anti-cancer assays. The methodologies have very broad applications for other biological pathways, such as small molecule immunological checkpoint inhibitor discovery.

Drug Development, IND Filing, and Clinical Trials

For the translation of late stage drug candidates into novel experimental therapeutics, scientists at the center can take advantage of the expertise and infrastructure from our collaborating institutions, including:

  • UCSD for pre-clinical ADME tox studies and clinical trials.
  • City of Hope for GMP/GLP facilities, IND filing, and clinical trials.
  • Riverside Community Hospital (Riverside) for clinical trials.
  • Desert Region Medical Center (Palm Springs) for clinical trials.
  • Cedars-Sinai Medical Center (Los Angeles, CA) for clinical trials.

In Vitro and In Vivo ADME Tox Studies

Identification of novel potential drug candidates requires careful fine-tuning on the pharmacological properties of lead candidates, not only to ensure potency and selectivity against the given target in vitro and in cellular assays, but also availability of the drug in vivo.

The center collaborates with the UC San Diego Drug Development Pipeline facilities led by Assistant Professor of Clinical Pharmacology Jeremiah Momper that will provide experimental data including: 

  • Metabolic stability (liver microsomes and hepatocytes)
  • CYP Inhibition or induction
  • in vivo pharmacokinetics
  • Metabolite identification
  • Protein binding
  • Drug Permeability
  • Physicochemical profiling
  • Bioanalytical Chemistry

This data will help our scientists to guide the hit-to-lead optimization process and in the selection of more suitable lead compounds for further efficacy studies in animal models.

GMP/GLP Facilities and IND Filing

For these activities, scientists at the Center for Molecular and Translational Medicine can take advantage of the City of Hope and Beckman Research Institute resources, services or expert consultation. In particular, the Chemical GMP Synthesis Facility (CGSF) is a state-of-the-art manufacturing resource for small and large molecule therapeutics for clinical trials. The facility is designed specifically to produce quantities of API on scales suitable for use in preclinical toxicology studies and in phase I and phase II clinical trials. The facility also provides investigators with a regulatory-compliant, cost-effective route towards bringing promising therapeutics to the clinic.

More Information 

General Campus Information

University of California, Riverside
900 University Ave.
Riverside, CA 92521
Tel: (951) 827-1012

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