Drug Discovery & Delivery Core (DDDC)

Target Validation and Structure Optimization

• Hit Identification and/or Virtual Screening (transcriptomic screens and structural docking screens)
• Bulk and Single Cell RNA Sequencing and Bioinformatics Analysis
• Screening with Virtual Combinatorial Peptide Library
• Hit-to-Lead
• Lead Optimizations
  • Fragment-based drug discovery
  • Structure-based drug discovery
• Chemical Synthesis
• ADMETox Assessment including perilymph collection and analysis
• Drug dosage form design
• Zebrafish screens in vivo 

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Fig. 2. Pipelines for screening and validation of small molecule or peptide hits in DDD CORE.

Our synthetic organic/medicinal chemists work closely with computational chemistry, bioscience and drug metabolism/pharmacokinetics (DMPK) teams to assemble a project-specific iterative drug discovery process that addresses key challenges at each stage of the project. Our close proximity and state of the art bioinformatics system allows a very rapid design-synthesize-test-analyze cycle to efficiently inform decision making.

The engine driving most small molecule discovery programs is the chemistry team.

Medicinal Chemistry

A journey towards a successful product launch initiates with high quality research integration within different disciplines. At DDDC, we have developed an international reputation at Creighton University in the field of medicinal chemistry with a strong track record of delivering clinical candidates. Our highly trained team of chemists are hand-picked from across the globe with the singular goal of bringing their experience to tackle most difficult synthetic challenges.

Our perfect mix of experience scientist includes research-staff with top notch expertise of progressing compounds from concept-to-lead-to-new chemical entity-to market; they provide appropriate support and guidance in the pursuit of our internal/external client’s goals, and continuous mentorship and training for the next generation of budding drug discovery scientist/research scholars. We value our clients and provide professional service with the aim that customers return to our medicinal chemistry facilities, again and again, to take advantage of our wide-ranging expertise and ability to conduct a hypothesis-driven approach with rapid data generation.

Our proficiency in library synthesis and scaffold design allows rapid access to many compounds for Structure Activity Relationships (SAR) evaluation.

Our easy access to database and analytical software allows our scientists to analyze data, identify trends and provide support for informed selection of the next synthetic targets.

Our experienced team provide early determination and assessment of critical ADMETox properties to guide lead discovery with goals of identifying well characterized drug candidates.

We have broad experiences in prodrug technology platforms, such as time- and pH-release driven strategies, while optimizing stability and solubility of the parent compound(s).

Synthetic Chemistry

Innovative and robust chemical synthesis is essential when seeking to generate novel patentable molecules with optimized biochemical profile.

When you have a dedicated team by your side capable of efficiently bringing your concepts and ideas to problem can make all the difference on handling synthetic challenges. Here at DDDC we are proud to have cultivated most dynamic synthetic chemistry group combining industry- and academia-based ideologies.

Our highly trained team of chemists are qualified to PhD level or higher. Each has been hand-picked from across the globe with the singular goal of bringing their experience to tackle most difficult synthetic challenges.

Peptide Chemistry 

Solid phase peptide synthesis of polypeptides at 0.25 mmol scale using a microwave-assisted automated peptide synthesizer.

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Fig. 3.  Inhibition of protein-protein interaction resulted in cell death. Virtual combinatorial tetrapeptide library was docked, using our GPU-cluster (A), on the dimerization interface 14-3-3 protein (B). The best binder peptide was chemically synthesized using our microwave peptide synthesizer (C) and promoted the apoptosis of skin cancer (Lovas, unpublished results and patent application).

Computation Chemistry

When the experimental three-dimensional structure of a target protein is not available, the structure is determined by homology modeling and refined by subsequent molecular dynamics (MD) simulations to be appropriate for docking simulations.

Analytical Chemistry

We have maintained highly efficient and most accurate analytical services for providing full confidence in the structure and purity of our molecules.

High quality synthetic and medicinal chemistry requires high quality analytical chemistry support. Having confidence in the structural characterization of your compounds is vital and allows efficient progression of a lead series. At DDDC we have invested heavily in the latest analytical tools to facilitate this process.

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Fig. 4.  A) AB Sciex QTrap 5500 mass spectrometer used for quantification experiments (ADME and PK/PD).  B) Example chromatogram with resolved novel antitubercular (North 2) and internal standard (warfarin) monitored through specific mass transitions.

Equipment 

DDDC Laboratories are equipped with fume hoods and sophisticated instrumentation, provide protein conjugations, multi-step chemical synthesis from milligram- to multigram scale.

We have the ability to provide access to the following equipment throughout the university:

• AB Sciex QTrap 5500 mass spectrometer (Fig. 4)
• Q Exactive Hybrid Quadrupole-Orbitrap™ Mass Spectrometer with Microflow UHPLC Systems
• 10XGenomics (Fig. 5)
• Zebrafish facilities (Fig. 6)
• 400-MHz NMR spectrometers
• Waters Synapt-G1 Q-TOF
• Agilent 1200s and Waters Acquity LC systems
• Preparative HPLC systems
• UPLC system (to be purchased)
• Hydrogen generator (to be verified)
• Combi-flash purification systems
• ion chromatography system
• Several flow reactors
• High-pressure autoclaves
• Electrochemistry Kit (to be verified)
• Multi-Scale Peptide Synthesizer (Dr Lovas)
• KF Titrator (to be verified)
• Labconco lyophilizer (Dr Jadhav Lab)
• -80℃ freezer
• Mettler Toledo ventilated weighing enclosure
• Centrifuges
• Liquid nitrogen storage
• High throughput chemistry

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Fig. 5. Single cell RNA seq results using 10x Genomics in the DDD Core. Top: Single cell suspensions are loaded onto the Chromium Controller. Bottom: Ordering of different mouse E10 forebrain cells (individual dots) along the pseudotime trajectory (collaboration with a Center Investigator).

Biomedical-science

Our in-depth knowledge of target biology, therapeutic area specialism, and experience of working collaboratively at each stage of the drug discovery pipeline allows the efficient design and implementation of tailored high-quality assays, which help to accelerate your drug discovery programs.

• Bulk and single cell RNA sequencing using 10XGenomics platform and subsequent bioinformatics analysis
• Assay development
• Understanding the assay purpose
• Identifying different assay formats
• Developing or sourcing optimal assay reagents
• Monitoring assay performance
• Options for automation and scaling
• Optimization
• Quality control via statistical validation
• Screening
• Fig: typical hit identification hit screening cascade (refer grant)
• Cellular assays
• Biochemical assays
• Biophysical assays