Kinase inhibitors are key therapeutic agents, particularly in oncology, yet their clinical efficacy is often hampered by off-target effects and limited understanding of their cellular target profiles.

Thirty years ago, mutations in the BRCA1 gene were first linked to hereditary breast and ovarian cancer, establishing a genetic basis for cancer development.

Triple-negative breast cancer (TNBC) is a subtype of breast cancer characterized by limited treatment options and unfavorable clinical outcomes. Therefore, the research described in this thesis focused on the exploration of novel targeted therapies for TNBC.

Promotores: Prof.dr. H.S. Overkleeft, Prof.dr. G.A. van der Marel

The research described in this thesis centered on retaining exo-β-glucosidases implicated in health and disease, in particular the human inherited lysosomal storage disorder, Gaucher disease (GD).

The molecular mechanisms that instigate a healthy cell to become malignant are fueled by (epi)genetic alterations in so-called driver genes.

This thesis describes the structural and biochemical characterization of the β-lactamase BlaC from Mycobacterium tuberculosis (Mtb), and the Alr and YlmE proteins from Streptomyces coelicolor A3(2).Mtb is the main cause of tuberculosis.

Promotor: H.S. Overkleeft, Co-promotor: M. van der Stelt

In this thesis, the discovery and optimization is described of chemical tools to study the N-acylethanolamine (NAE) biosynthetic pathway.

The indane (2,3-dihydro-1H-indene) ring system is an attractive scaffold for biologically active compounds due to the combination of aromatic and aliphatic properties fused together in one rigid system.

Key publications of the Computational Drug Discovery group

Due to their central physiological roles in living organisms, retaining beta-glycosidases have been the subject of tremendous research efforts to examine their structure/function relation using numerous biophysical and biochemical approaches.

In this thesis, a system pharmacology approach, integrating metabolomics, pharmacology and chemical biology, was applied to understand and modulate the endocannabinoid system across different model systems (cells, zebrafish, mice and humans).

Drug development is a time- and resource-consuming process that starts with the discovery and validation of a (protein) target that contributes to pathogenesis or disease progression.

An integrated approach for the simultaneous prediction of polypharmacology and binding affinity/potency of small molecules.

Research at the BIOSYN group is comprised of the following research themes:

The Leiden Academic Centre for Drug Research (LACDR) received no less than three awards during the Figon Dutch Medicine Days. Bas Goulooze won the PhD Prize for best PhD candidate, Natalia Ortiz Zacarías and Huub Sijben both received a poster prize. ‘Scientists must be able to communicate their research…

While bioinformatics methods deal with the analysis of sequence information (be it proteins or DNA), the field of cheminformatics is concerned with the analysis of small-molecule datasets.

BlaC is the β-lactamase of Mycobacterium tuberculosis. We show that it can recover from inhibition by clavulanic acid and that phosphate helps it do so.

Activity-based protein profiling (ABPP, also termed chemical proteomics), is one of the pillars of chemical biology, and at LED3 we have taken it to the next level. ABPP allows the assessment of protein function in live cells and tissues, which means that the activity of a complete protein family can…

Pharmaceutical research should make more use of data science, says Gerard van Westen, postdoctoral fellow at the Leiden Academic Centre for Drug Research (LACDR). ‘If we want to have better drugs, we should start with data.’

Chemical biology research at the Leiden Institute of Chemistry is aimed at understanding biological processes at the molecular level to strengthen the knowledge base of human health and disease. The approach to achieve this goal is a fundamental chemical one; with the aid of chemical probes biological…

Chemical biology research at the Leiden Institute of Chemistry is aimed at understanding biological processes at the molecular level to strengthen the knowledge base of human health and disease. The approach to achieve this goal is a fundamental chemical one; with the aid of chemical probes biological…

Research question

Promotor: H.S. Overkleeft, Co-promotor: M. van der Stelt

This thesis describes the synthesis and biological evaluation of TLR2/6, TLR4, TLR7/8 and TLR9 ligands, of which the activity can be conditionally controlled.

This thesis describes the development and optimization of the first molecular tools to study the enzyme PLA2G4E.

The Protein Centre can supply you with purified proteins that are essential for many experiments, ranging from in vitro inhibitor screening and enzymatic analysis to manipulation of life cells.

The current projects of the Molecular Physiology group focus on proteins of the endocannabinoid system, kinases and antibacterial targets. MSc- and BSc-students can contact Jessica van Krimpen-Kraaijenoord to apply for research internships.

Ever since the FDA approved the drug bedaquiline, which interferes with the bioenergetics of Mycobacterium tuberculosis by inhibiting the activity the F0F1-ATP synthase, respiratory-chain enzymes have been an active target space for the discovery of new antibiotics. To aid in this pursuit, we aim to…

The precise psychobiological mechanisms leading to chronic physiological stress responses have not been sufficiently explained, although stress is a major risk factor for disease and early death. A problem for conventional stress theory is that most of these responses seem to occur in situations without…

Promotor: H.S. Overkleeft, Co-Promotor: B.I. Florea

The work described in this thesis focuses on the development of linear or cyclized peptide probes against protein N-methyltransferases to characterize their specific binding behavior, providing further binding details for inhibitory activity study.

The research in the Biosyn group is focused on the design, synthesis and function of the four major types of biomolecules: nucleic acids, carbohydrates, peptides and lipids and hybrid structures thereof. These biomolecules and their derivatives are used in drug discovery and chemical biology, to develop…

Multiple Sclerosis, Parkinson’s and Alzheimer’s disease are the most common neurodegenerative disorders. Unfortunately, no effective treatments are currently available to halt the progression of these neuroinflammatory diseases [1].

How can we develop new chemical biology tools and approaches to understand and interfere with glucosylceramide metabolism in relation to Gaucher disease?

What is the most effective way to eliminate tumour cells? The DNA repair mechanism could play an important role in increasing the effectiveness of chemotherapy in the fight against cancerous cells. If we are to influence this mechanism, we need fundamental knowledge about how the mechanism works.

The aims of the project are to: further clarify 'inhibition by safety'; explore and describe all possible sagety factors, with a special focus on the primary human safety source: social connectedness; reviewing prolonged stress responses without stressors.

Deficiency of glucocerebrosidase (GBA) underlies Gaucher disease, a common lysosomal storage disorder. Carriership for Gaucher disease has recently been identified as major risk for parkinsonism. Presently, no method exists to visualize active GBA molecules in situ. We here report the design, synthesis…

The research presented in this thesis explores the chemotherapeutic potential of metal-based compounds as chemotherapy agents, with an initial focus on the synthesis and DNA interaction studies of platinum and palladium compounds utilizing the [Pt(bapbpy)]2+ scaffold. The study identifies intercalation…

This thesis tackles the urgent challenge of antimicrobial resistance (AMR) through the design of novel antibacterial agents.

Diacylglycerol lipases (DAGLα and DAGLβ) convert diacylglycerol to the endocannabinoid 2-arachidonoylglycerol. Our understanding of DAGL function has been hindered by a lack of chemical probes that can perturb these enzymes in vivo.

Leiden chemists, together with colleagues at the University of York (UK) and Technion (Israel) have discovered a small, sugar-like molecule that maintains the integrity of tissue around a tumour during cancer. This molecule prevents tumour cells from spreading from the primary cancer site to colonise…

Can the conditioning paradigm be used for checkpoint inhibition cancer treatment?

How can efficient chemical synthesis and clinical microbiology be combined to identify new antibiotics against Clostridioides difficile infections?