Synthesis and Analysis (S&A)
Research programme
Mission statement
The programme S&A combines expertise in analytical chemistry with that in medicinal chemistry and biomonitoring.
The programme performs preclinical and clinical studies in order to translate fundamental new chemical entities
and analytical methods into clinical practice. Bioinformatics plays an important role in this process covering molecular
modelling of drug-protein structures as well as processing of hyper-dimensional data from ‘omics’ experiments.
The programme forms the link between chemistry and biomedicine within GUIDE and encompasses three sub-programmes.
Analytical Biochemistry
The research group Analytical Biochemistry focuses on the analysis of biological macromolecules with special emphasis on proteins and peptides
according to the following research lines.
Analysis of Biomarkers -
The biomarker discovery research line is pursued in collaboration with a number of clinical and informatics research
groups in the context of large national and international (European) projects. The line is divided into the following main
areas
- discovery of biomarkers for pulmonary disease, notably Chronic Obstructive Pulmonary Disease (COPD)
- discovery of biomarkers for cancer (cervical cancer, prostate cancer), c) discovery of biomarkers for neurological disorders (multiple sclerosis) and d) discovery of biomarkers for obesity and diabetes type II.
Data Processing and Analysis -
The bioinformatics research line is closely related to the analytical activity of the research group and focuses on preprocessing
and analysis of mass spectrometry-derived ‘omics’ data. In collaboration with IBM we are developing
complete data pre-processing pipelines for LC-MS data used in biomarker discovery projects with a focus on the development
of novel algorithms to correct for non-linear retention time shifts in complex LC-MS data sets with high
concentration variation. In collaboration with chemometrics and statistics groups we are involved in development and
assessment of classification methods. In addition we are developing a framework to integrate newly developed tools,
including data management software, using local and national computation infrastructures. Our activity is embedded
within national bioinformatics initiatives, such us the Netherlands Bioinformatics for Proteomics Platform, The Netherlands
Bioinformatics Center (NBIC) and the Netherlands Proteomics Center (NPC).
Chemical Proteomics -
This research line focuses primarily on activity-based profiling of metalloproteases comprising members of the matrix
metalloprotease (MMP) and the membrane-bound “A Disintegrin and MetalloProtease” (ADAM) families.
Another focus is the development of novel stable isotope labelling reagents for proteins, peptides and metabolites.
These projects are based on close collaborations with the organic chemistry group of Prof. Overkleeft (Leiden
University). We are furthermore investigating the possibilities of combining electrochemical reactions with mass spectrometry
to simulate Phase-I metabolic reactions and to promote peptide and protein cleavage. Our research on posttranslational
modifications focuses on oxidative stress and notably the analysis of nitro-tyrosine-containing proteins
and peptides.
Pharmaceutical Analysis
The sub-programme Pharmaceutical Analysis maintains not only an established knowledge base of modern, proven analytical methodologies, but also strives to develop completely new principles of analysis and detection. This group continues to focus on the development of analytical applications in the pharmaceutical sciences using new combinations of established instrumentation and approaches. The integration of sample pretreatment and analysis into single systems has been of particular interest, as has the coupling of various analysis techniques with mass spectrometric detection.
In the area of fundamental analytical development, a lab-on-a-chip line of research focusing on the combination of state-of-the-art microtechnologies with biology and biochemistry is present. This branch of modern chemistry, also known as microfluidics , involves the application of microtechnologies to chemical processing and control on a very small scale. Networks of hair-fine channels formed in planar glass, silicon, or plastic surfaces are the essential tools used. The sub- m L liquid handling which is made possible by this technology is revolutionary, and will lead to new tools for the pharmaceutical sciences and the life sciences in general.
Biomonitoring and Sensoring/Medicanal Chemistry
The sub-programme Biomonitoring and Sensoring focuses on the development, application and elucidating underlying mechanisms of in vivo monitoring techniques such as microdialysis and microsensors in experimental animals and humans. In addition our objective is the furtherance of replacement, reduction and refinement of animal experiments.
The aim of sub-programme Medicinal Chemistry is to develop the science of medicinal chemistry and CNS pharmacology in order to create the proper prerequisites for a successful drug discovery programme for diseases in the CNS. We anticipate discovering new, CNS active and receptor-subtype selective compounds, potentially useful as research tools and/or as new treatments against diseases in the CNS, e.g. Parkinson’s disease, schizophrenia, anxiety, depression and drug abuse. In particular, the fine-tuning of the structure activity relationships (SAR) studies is very important for the research group.
Applying and developing the microdialysis technique into a very useful tool for measuring, simultaneously, both pharmacodynamic and pharmacokinetic properties of our most promising drug candidates has become a central part of our drug development programme.
This combined technique will provide a valuable contribution to the difficult selection procedure of a drug candidate in the pharmaceutical industry today. The new techniques for drug screening (high throughput screening, HTS) frequently delivers too many candidate drugs to choose from. After having reduced the number of drug candidates to about 10, our microdialysis technique can be used to further narrow this number. However, and most importantly, well trained medicinal chemists and pharmacologists work intimately together in this difficult task of selecting the best drug candidate for development.
Contact
Programme leader
Name: Prof.Dr. R. Bischoff
Phone: +31 (0)50 363 3338
e-mail Prof. Bischoff
Secretariat
Name: Ms. J. Meindertsma
Phone: +31 (0)50 363 3336
e-mail Ms. Meindertsma
