Monoacylglycerol lipase (MAGL) is the principal enzyme responsible for hydrolysis of the endocannabinoid 2-arachidonoylglycerol (2-AG). MAGL inhibition provides several potential therapeutic opportunities, including anti-nociceptive, anti-inflammatory and anti-cancer activity.

In this thesis an activity-based probe was discovered that could visualize the activity of PLAATs. With an optimized gel-based ABPP assay in hand, screening of a compound library led to the discovery of alpha-ketoamides as a hit for PLAAT3.

Less than 1 in 10 drug candidates that enter phase 1 clinical trials actually gets approved for human use.

Large parts of the research described in this Thesis aims at the development of oligopeptide-masked toxins and their in situ immunoproteasome-mediated activation.

The main focus of the thesis is the discovery and development of novel inhibitors of bacterial metallo-β-lactamases (MBLs).

The chemical synthesis of inhibitors and probes targeting endo-glycosidases.

NNMT wordt beschouwd als een nieuw potentieel farmacologisch doelwit in de behandeling van een verscheidenheid van kankers, stofwisselingsziekten en andere pathologieën. Het toenemend aantal publicaties waarin de rol van NNMT bij ziekten wordt opgehelderd, heeft op zijn beurt de ontwikkeling van krachtige…

Supervisor: Anna Vlachodimou

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

The clinical potential of applying synthetic lethality to cancer treatment is famously demonstrated by the BRCA1/PARP1 paradigm: a tumor specific defect in BRCA1 – a component of the DNA double-strand break (DSB) repair pathway homologous recombination (HR) – results in a remarkable sensitivity to PARP1…

This Thesis describes the design, synthesis and evaluation as glycoprocessing enzyme inhibitors of focused libraries of iminosugars.

Promotores: H.S. Overkleeft, G.A. van der Marel, Co-Promotor: J.D.C. Codee

The disease acute myeloid leukemia (AML) is characterized by fast progression and low survival rates.

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

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

This thesis describes the design and development of subunit‐selective inhibitors of particular catalytically active subunits of human constitutive proteasomes and immunoproteasomes.

Source: J Cheminform, Volume 7, Issue 1 (2015)

Glycosidases are essential in fundamental biological processes and are responsible for the degradation of most (oligo)saccharides, glycolipids and glycoproteins.

Source: PLoS ONE, Volume 10, Issue 3 (2015)

Supervisor: Xue Yang

N-acylethanolamines (NAEs), which include the endocannabinoid anandamide, represent an important family of signaling lipids in the brain. The lack of chemical probes that modulate NAE biosynthesis in living systems hamper the understanding of the biological role of these lipids.

Promotor: J.P. Abrahams, Co-Promotor: N.S. Pannu

The drug BIA 10-2474 inhibits fatty acid amide hydrolase (FAAH), a lipase that degrades a specific endocannabinoid. On the basis of this activity, BIA 10-2474 was being developed as a potential treatment for anxiety and pain. In a phase 1 trial of the drug, one subject died, and four others suffered…

Source: Br. J. Pharmacol., Volume 172, Issue 3, pp. 940-55 (2015)

Science, Leiden Institute of Chemistry (LIC)

The research described in this thesis focused on identifying novel drug targets and synergistic combinations for triple-negative breast cancer (TNBC), a virulent subtype of breast cancer with a dismal prognosis and limited therapeutic options.

To this day, all cyclophellitol-based inhibitors and ABPs have been close analogues of their natural substrate counterparts. As a result, these probes showed high selectivity towards their target glycosidases.

Promotores: B. van de Water; P. Hogendoorn; J. Bovée Co-Promotor: E.H.J. Danen

Glycosidases are important enzymes in the turnover of polysaccharides and glycoconjugates, and are involved in a range of human pathologies including genetic disorders such as Gaucher and Pompe disease, but also in various cancers.

The studies presented in the work show the potential of the integrative use of biophysical data in defining the structural basis of protein interactions.

Promotores: H.S. Overkleeft; G.A. van der Marel Co-Promotor: B.I. Florea

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

PhD Defence

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

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.

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).

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

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.

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

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.

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.

PhD Defence

PhD Defence

PhD Defence

PhD Defence