Inactivating mutations in BRCA1 or BRCA2 genes predispose to several types of cancer.

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.

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

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

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

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.

Supervisor: Anna Vlachodimou

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

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

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)

Diacylglycerol lipase (DAGL)-α and -β are enzymes responsible for the biosynthesis of the endocannabinoid 2-arachidonoylglycerol (2-AG). Selective and reversible inhibitors are required to study the function of DAGLs in neuronal cells in an acute and temporal fashion, but they are currently lacking.…

Supervisor: Xue Yang

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

A model method: A strategy that combines a knowledge-based in silico design approach and the development of novel activity-based probes (ABPs) for the detection of endogenous diacylglycerol lipase-α (DAGL-α) is presented. This approach resulted in the rapid identification of new DAGL-α inhibitors with…

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)

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.

Phosphorylation affects all four major biomolecules – proteins, lipids, carbohydrates and nucleic acids – and plays a pivotal role in the most fundamental cellular functions.

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

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

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.

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

PhD Defence

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

PhD Defence

Lecture

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

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).

Key publications of the Computational Drug Discovery group

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.

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.

PhD Defence

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…

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.