Henriette Willems

• PhD
• Senior Research Associate at University of Cambridge

The protein kinase NUAK1 has been implicated in various biological functions including cell adhesion, migration and proliferation. Genetic reduction of NUAK1 expression has notably been shown to lower total levels of human tau in a tauopathy mouse model, identifying this kinase as a potential therapeutic target for neurodegenerative disease. In thi...

Drug discovery is a complex and resource-intensive process, with significant time and cost investments required to bring new medicines to patients. Recent advancements in generative machine learning (ML) methods offer promising avenues to accelerate early-stage drug discovery by efficiently exploring chemical space. This paper addresses the gap bet...

Discovery and structural biology of PI5P4K ligands

Neuropathology is often mediated by interactions between neurons and glia that cannot be modeled by monocultures. However, cocultures are difficult to use and analyze for high-content screening. Here, we perform compound screening using primary neuron-glia cultures to model inflammatory neurodegeneration, live-cell stains, and automated classificat...

The phosphatidylinositol 5-phosphate 4-kinases (PI5P4Ks) are therapeutic targets for diseases such as cancer, neurodegeneration and immunological disorders as they are key components in regulating cell signalling pathways. In an effort to make probe molecules available for further exploring these targets, we have previously reported PI5P4Kα-selecti...

Sheffield 2023 conference presentation on the virtual screening strategy used to discover PI5P4K inhibitors, and analysis of the crystal structures obtained for the lead compounds

The phosphatidylinositol 5-phosphate 4-kinases (PI5P4Ks) play a central role in regulating cell signalling pathways and, as such, have become therapeutic targets for diseases such as cancer, neurodegeneration and immunological disorders. Many of the PI5P4Kα inhibitors that have been reported to date have suffered from poor selectivity and/or potenc...

Owing to their central role in regulating cell signaling pathways, the phosphatidylinositol 5-phosphate 4-kinases (PI5P4Ks) are attractive therapeutic targets in diseases such as cancer, neurodegeneration, and immunological disorders. Until now, tool molecules for these kinases have been either limited in potency or isoform selectivity, which has h...

An overview of three public drug databases to mine for chemical probes and two free tools to analyse data with chemical structures

Development of Selective Phosphatidylinositol 5-Phosphate 4-Kinase γ Inhibitors

This presentation discusses computational chemistry tools and methods for drug discovery that are free or of low cost. This work was presented as a webinar hosted by eMolecules. The recording is available from https://www.gotostage.com/channel/emolecules-scientific-webinar-series?fbclid=IwAR25oKB-CYbYHUn3zUUVqfO_28xJvbCzEcyKnJeOarvxBo3-0tMMUqRXEDY

Bifunctional molecules known as PROTACs simultaneously bind an E3 ligase and a protein of interest to direct ubiquitination and clearance of that protein, and they have emerged in the past decade as an exciting new paradigm in drug discovery. In order to investigate the permeability and properties of these large molecules, we synthesized two panels...

An increasing number of new drugs have their origin in small biotech or academia. In contrast to big pharma, these environments are often more limited in terms of resources and this necessitates different approaches to the drug discovery process. In this perspective, we outline how computational methods can help advance drug discovery in a setting...

This presentation describes the identification of potent and selective inhibitors of PI5P4Kalpha and gamma through virtual screening.

The KEAP1/NRF2-mediated cytoprotective response plays a key role in cellular homoeostasis. Insufficient NRF2 signalling during chronic oxidative stress may be associated with the pathophysiology of several diseases with an inflammatory component, and pathway activation through direct modulation of the KEAP1-NRF2 protein-protein interaction is being...

This presentation describes our efforts to create an annotated library for phenotypic screening by mining the ChEMBL23 database and the issues we encountered along the way. A key decision point in the process was the definition of selectivity: how many targets does a compound need to be tested at before selectivity is a meaningful concept? What is...

Fatty acid binding protein (FABP6) is a potential drug discovery target, which, if inhibited, may have a therapeutic benefit for the treatment of diabetes. Currently, there are no published inhibitors of FABP6 and, with the target believed to be amenable to fragment-based drug discovery, a structurally enabled program was initiated. This program su...

KEAP1 is the key regulator of the NRF2-mediated cytoprotective response, and increasingly recognized as a target for diseases involving excessive oxidative stress. Pharmacological intervention to date has focussed on molecules that decrease NRF2-ubiquitination through covalent modification of KEAP1 cysteine residues, but such electrophilic compound...

The discovery and development of a new drug are parts of a multistep process that starts with the detailed analysis of the disease to be investigated. The next step is the identification of the key biological molecules that are involved in the disease process whereby modulation of these molecules, usually proteins, will likely have a therapeutic ef...

ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.

ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.

Reflex is a recent algorithm in the de novo ligand design software, SkelGen, that allows the flexibility of amino acid side chains in a protein to be taken into account during the drug-design process. In this paper the impact of flexibility on the solutions generated by the de novo design algorithm, when applied to carboxypeptidase A, acetylcholine...

From a set of weakly potent lead compounds, using in silico screening and small library synthesis, a series of 2-alkyl-3-aryl-3-alkoxyisoindolinones has been identified as inhibitors of the MDM2-p53 interaction. Two of the most potent compounds, 2-benzyl-3-(4-chlorophenyl)-3-(3-hydroxypropoxy)-2,3-dihydroisoindol-1-one (76; IC(50) = 15.9 +/- 0.8 mi...

A de novo design approach to generating novel estrogen receptor (ER) ligands is described. The SkelGen program was used to generate ligands in the active sites of seven crystal structures of ERalpha. Seventeen high-scoring, diverse structures were selected from the SkelGen output and synthesized without introducing any modifications to the structur...

A series of 2-N-alkyl-3-aryl-3-alkoxyisoindolinones has been synthesised and evaluated as inhibitors of the MDM2-p53 interaction. The most potent compound, 3-(4-chlorophenyl)-3-(4-hydroxy-3,5-dimethoxybenzyloxy)-2-propyl-2,3-dihydroisoindol-1-one (NU8231), exhibited an IC50 of 5.3 +/- 0.9 microM in an ELISA assay, and induced p53-dependent gene tra...

A major difficulty in structure-based molecular design is the prediction of the structure of the protein-ligand complex because of the enormous number of degrees of freedom. Commonly, the target protein is kept rigid in a single low-energy conformation. However, this does not reflect the dynamic nature of protein structures. In this work, we invest...

The design and synthesis of N-(3-indolylmethyl)-3-benzyl-2-azabicyclo[2.2.1]heptane-2-carboxamide (3) as a conformationally constrained non-peptide β-turn mimetic is described. Compound 3 is shown to mimic the Trp and Phe side chain conformation and the overall dipole moment of MEN10627 (2), a cyclic hexapeptide with a high NK-2 affinity. The tachy...

The design and synthesis of conformationally constrained, nonpeptide templates (1,1,6-trisubstituted indanes) which allow the incorporation of two adjacent amino acid side chains, plus a third binding group in an orientation similar to that found in alpha-helices are reported. Six racemic and two homochiral Phe-Phe and Trp-Phe mimetics were synthes...

The design and synthesis of conformationally constrained, non-peptide templates (3-substituted pyrrolidines) which allow the incorporation of two adjacent amino acid side-chains in an orientation similar to that found in the i+1 and i+1 positions of a β-turn are reported. The NK2 tachykinin receptor affinity of a Trp-Phe mimetic (7a) which mimics t...

The design and synthesis of conformationally restrained, non-peptide templates (1,6-disubstituted indanes) which allow the incorporation of two adjacent amino acid side-chains in an orientation similar to that found in alpha-helices is reported.

The design and synthesis of conformationally constrained, non-peptide templates (trisubstituted indanes) which allow the incorporation of two adjacent amino acid side-chains plus a third binding group in an orientation similar to that found in alpha-helices is reported. The tachykinin receptor affinity of various Phe-Phe and Trp-Phe mimetics were d...

2-Phenoxypropene (2) was applied as a novel protective reagent of chiral alcohols, yielding 2-phenoxy-isopropyl (PIP) ethers. Introduction and cleavage of the protective group was achieved under mild conditions.