Moulder Center for Drug Discovery Research at the Temple University School of Pharmacy

The Moulder Center for Drug Discovery Research was established in 2009 with a donation from Lonnie and Sharon Moulder, alumni of the Temple University School of Pharmacy. Their intention was to support the creation of a multidisciplinary research hub for the development of scientific discoveries identified by Temple University faculty and scientists. Today’s Moulder Center, the manifestation of this intention, attracts funding from a variety of sources, including the U.S. government, private foundations, alumni, industry partners, and other advocates.

At the Moulder Center, Temple University graduate and undergraduate students work alongside experienced drug discovery scientists, learn modern techniques required for the successful identification of the next generation of therapies, and play key roles in research collaborations. As members of the team, students gain expertise in using research tools, including parallel synthesis, high throughput screening, molecular biology, and pharmacokinetics. 

Get to know our team

Objectives

Drug Design and Lead Optimization
• Small molecule therapeutics in multiple disease areas
• Chemical probes to test biological hypotheses
• Tools to help understand relevant physiological processes

Facilitate collaborative research
• Temple University collaborators
• External collaborators in the U.S. and abroad

Translational Medicine
• Bridging the gap between pre-clinical and clinical research

Training in Modern Drug Discovery and Development
• Students, Faculty, & Future Researchers

Research Areas

• GLT-1 and Cocaine
• GLT-1 and Cerebral Palsy
• D3 modulators and psychostimulant abuse
• Allosteric PARP1 inhibitors and cancer
• CDK-9 inhibitors and cancer
• DNA polymerase theta (POLQ) inhibitors and cancer
• Lyposomal storage disease therapeutics
• RAD52 inhibitors and cancer
• RnpA inhibitors as antibacterial agents

Facilities, Equipment, and Capabilities

The Moulder Center has eight laboratories comprising approximately 9,000 square feet. 

Medicinal Chemistry
We have 22 fume hoods dedicated to the synthesis, purification, and study of organic molecules. The chemistry laboratories are designed to handle mg to kg scale small molecule synthesis. Parallel synthesis platforms are also available for the preparation of either diversity driven or focused libraries of 10s to 1000s of compounds on 10 – 100 mg scale. They are suitable for large scale synthesis to meet the needs of PK studies, in vivo animal studies, and CGMP production. 

In addition to the standard laboratory glassware and equipment (e.g. rotovaps, balances, vacuum pumps, etc.), the Moulder Center labs are equipped with:
• Gilson 215 semi-preparative HPLC system
• Gilson GX-281 preparative HPLC system
• Genevac EZ-2Evaporator
• CEM Explorer microwave
• Teledyne Isco Combiflash Rf system (2)
• Grace Reveleris HPLC chromatography system with ELSD detection
• Walk in fume hood capabilities for large scale chemistry

Specific Analytical Instrumentation and Equipment Includes:
• Nuclear Magnetic Resonance (NMR) Instruments:
    • Bruker 400 MHz NMR (School of Pharmacy)
    • Bruker 300, 400 MHz (College of Science and Technology
    • GE 500 MHz (College of Science and Technology)
• Mass Spectroscopy:
    • Agilent HPLC/MS ESI with PDA
    • API 4000 LC/MS/MS
• FT-IR Perkin-Elmer Model 1625.
• X-ray Crystallography via the Dept. of Chemistry, U. of Penn.
• Shimadzu UPLC system LC-20AD suitable for HPLC and GPC.
• TA Instruments Q200 modulated differential scanning calorimeter with RCS cooling unit (range 90°C-400°C).
• Malvern ZS Nano particle size analyzer with zeta potential measurement.

In Vitro Assay Development and Screening Capabilities

The high throughput screening capabilities are built around two Janus Automated Workstations (Varipsan and MDT) capable of supporting 96-well or 384-well platforms. The system supports multiple in vitro and cellular assay paradigms for the study of enzymes, receptors, ion channels and transporter proteins. The Envision 2104 Multilabelreader provides capabilities to detect diverse platforms including absorbance, fluorescence, luminescence, Alpha Screen® and fluorescence polarization. High throughput radiolabel binding and uptake assays are supported with a Perkin Elmer Topcount NXT-HTS Microplate scintillation counter. In addition, label free methods using LC/MS/MS are routinely utilized for in vitro drug metabolism studies. High throughput screening is supported by a 40,000 member small molecule diversity-based screening library which includes linear and cyclic peptides as well as the Prestwick 1,200 member library of FDA approved drugs. The center recently licensed and implemented the Dotmatics Informatics Platform (Dotmatics, Ltd) to support the chemical database, high throughput screening data management, structure activity relationship (SAR) analysis, and data visualization. The facility has three tissue culture suites to support development of cell based assay and maintenance of cultured cells.

In Vivo
Micro dissection
Behavioral assessment
    Conditioned place preference
    Analgesia and tolerance

Ex Vivo
    Radio ligand
    Homogenate binding
    Autoradiography
    Rubidium efflux
       Neurotransmitter release
    Receptor profiling
    Drug affinities
       Functional responses
    Subunit composition
    Quantification and distribution
    Protein and neuron characterization
    Western blotting
    Immunohistochemistry
    HPLC
    Synaptosomal preparations

Other Specialized Capabilities
    Pharmacogenomic Analysis of SNP’s
    Copy Number Variations
    Cell-based assays
    cytotoxicity
    apoptosis
    caspase activation
    cell viability
    In-vitro metabolism
    Pre-clinical PK

Biotherapeutics 

The Biotherapeutics Laboratory brings state-of-the-art discovery capabilities for protein-based drugs to the Moulder Center.  Drawing on over 30 years of academic and industrial experience in prokaryotic, eukaryotic and viral molecular genetics, heterologous protein expression and therapeutic antibody discovery and engineering, we utilize phage display technology as our primary protein discovery platform.  In mid-2014 we completed a licensing agreement with MorphoSys AG for their “Ylanthia” Fab display phage library, making the Moulder Center the only academic group in the world with access to this powerful industrial-quality human antibody discovery platform.  Protein purification is carried out with a GE ÄKTA Explorer FPLC, and rapid clone screening is facilitated by a Hamilton Microlab STARlet liquid handler, BioTek EL406 plate washer/dispenser with magnetic microbead capability, an EnVision  multi-label plate reader, and a Luminex MAGPIX fluorescent microbead imager.  Protein-protein interaction analysis is carried out by biolayer interferometry using a ForteBio BLItz and by surface plasmon resonance using a Biacore 3000.

Solid Phase Peptide Synthesis

The Moulder Center is equipped with state of the art Solid Phase Peptide Synthesis (SPPS ) equipment, including the CEM Liberty 1 Microwave Peptide Synthesizer. Comprehensive expertise in peptide synthesis and purification, as well as identification and characterization of proteins from recombinant or biofluidic sources are available.

In Vitro ADME and Pharmacokinetics

The Moulder Center for Drug Discovery Research is equipped to provide a wide range of in vitro ADME/PK studies, drug metabolism studies and in vivo Pharmacokinetics (PK) studies in support of drug discovery programs.

In Vitro Assays
Microsomal Stability – Human and preclinical species.
Hepatocyte Stability – Determine direct conjugation or metabolism by aldehyde oxidase.
Unbound fraction assays – Equilibrium dialysis and LC/MSMS analysis and interpretation.
CYP inhibition assays - CYP3A4, CYP2D6 and CYP2C9.
Permeability assays – CACO-2 and MDCK for correlation with absorption and BBB.
Metabolite ID – Tissue preparations, expressed enzymes and LC/MSMS identification.

In Vivo Assays
Preclinical Pharmacokinetics – Mouse and rat studies (IV and oral) to determine
Volume of distribution
Clearance
Half-life
Bioavailability
CNS Penetration - Mouse and rat with SC, IP, or IV administration. 

Proteomics
The 1,900 sq. ft. Temple Proteomics Research Facility provides accessible proteomics capability for biological and biomedical research. This research facility has state-of-the-art instrumentation and is supported by staff with expertise in proteomics, tissue microanalysis and relevant bioinformatics.  Services provided include expression profiles, protein identification, posttranslational modification, characterization, isolation of individual cells from tissues, protein and peptide separations, capillary electrophoresis and multidimensional protein identification (MudPIT). Using a variety of techniques, the facility is capable of generating high fidelity data for biomarker discovery, drug targets and studies on the pathogenesis of disease. Major equipment includes:
• Bruker autoflex mass TOF/TOF mass spectrometer
• Bruker HCT ion trap mass spectrometer coupled with Agilent nonoLC system
• Etlan Maldi-TOF Pro
• Shimadzu Xcise automated robotic system for gel processing
• Applied Biosystem Voyager workstation MALDI-TOF mass spectrometer
• Amersham Biosciences ETTAN DIGE 2D gel electrophoresis system and Multiphor 2D gel analysis system
• Beckman Coulter MDQ capillary system with laser induced fluorescence detector
• Photodiode array detector and Finnigan LCQ mass spectrometer
• Arcturus Veritas laser capture microdissection system
• Various HPLC systems with photodiode and scanning fluorescence detector