The 17th EFMC Short Course on Medicinal Chemistry on Small Molecule Protein Degraders

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The 17th EFMC Short Course on Medicinal Chemistry on Small Molecule Protein Degraders

The 17th EFMC Short Course on Medicinal Chemistry this year focused on Small Molecule Protein Degraders, and the opportunities and challenges that they present as a novel modality of drug design and development. This conference report summarizes the successful event, the lectures delivered, and the topics discussed.


Abstract

The 17th EFMC Short Course on Medicinal Chemistry took place April 23–26, 2023 in Oegstgeest, near Leiden in the Netherlands. It covered for the first time the exciting topic of Targeted Protein Degradation (full title: Small Molecule Protein Degraders: A New Opportunity for Drug Design and Development). The course was oversubscribed, with 35 attendees and 6 instructors mainly from Europe but also from the US and South Africa, and representing both industry and academia. This report summarizes the successful event, key lectures given and topics discussed.

Thermal Performance Analysis of a Mounded Liquid Ethylene Storage Tank

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Thermal Performance Analysis of a Mounded Liquid Ethylene Storage Tank

A model is established to investigate the temperature field distribution of a mounded liquid ethylene storage tank system under long-term placement. The effects of external environment, number of storage tanks, tank spacing, and thickness of the cold insulation structure on the temperature field distribution are analyzed. Reference for the design of heat tracing devices in such tank systems is provided.


Abstract

A model including the tank body and the external environment is developed to investigate the temperature field of a mounded liquid ethylene storage tank system during long-term placement. Since the external environment always changes, it is introduced by writing user-defined functions (UDFs). The effects of external environment and structural parameters on the temperature field are analyzed to provide reference for the design of the heat tracing devices of the storage tank system. The results indicate that the increase of tank quantities substantially reduces the outer-surface temperature of the cold insulation structure. The increase in tank spacing and thickness of the cold insulation structure weakens the interaction of adjacent tanks and raises the outer-surface temperature of the cold insulation structure.

Insights into the Self‐Filling Effects of Branched Isopropyl Groups on the Conformational and Supramolecular Properties of Isopropoxyprism[6]arene

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Insights into the Self-Filling Effects of Branched Isopropyl Groups on the Conformational and Supramolecular Properties of Isopropoxyprism[6]arene

The Front Cover shows images of buds and blossomed waterlilies. As the sun favours the blossoming of the waterlilies, a molecular recognition event triggers a conformational change of the isopropoxy-prism[6]arene from a closed to open structure. Cover design by Rocco Del Regno, Carmine Gaeta and Silvano Geremia. More information can be found in the Research Article by R. Del Regno, S. Geremia, C. Gaeta et al.


Development of Photoswitchable Tethered Ligands that Target the µ‐Opioid Receptor

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Converting known ligands into photoswitchable derivatives offers the opportunity to modulate compound structure with light and hence, biological activity. In doing so, these probes provide unique control when evaluating G-protein-coupled receptor (GPCR) mechanism and function. Further conversion of such compounds into covalent probes, known as photoswitchable tethered ligands (PTLs), offers additional advantages. These include localization of the PTLs to the receptor binding pocket. Covalent localization increases local ligand concentration, improves site selectivity and may improve the biological differences between the respective isomers. This work describes chemical, photophysical and biochemical characterizations of a variety of PTLs designed to target the µ-opioid receptor (µOR). These PTLs were modeled on fentanyl, with the lead disulfide-containing agonist found to covalently interact with this medically-relevant receptor.

A Redox‐neutral Nickel‐catalysed Sulfonylation of (Hetero)aryl Boronic Acids with 2‐Chlorothiazoles

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A redox-neutral nickel-catalysed sulfonylation for arylsulfone synthesis were developed. (Hetero)aryl boronic acids reacted with potassium metabisulfite (K2S2O5) and readily available 2-chlorothiazoles in the presence of air-stable Ni(OTf)2 and 4,4-di-tert-butyl bipyridine (dtbbpy) as a commercially available ligand to produce the corresponding 2-sulfonylthiazoles in moderate to excellent yields. This practical protocol tolerates a wide range of substrates including boronic acids and 2-chloro(benzo)thiazoles without additional bases, allowing the direct synthesis of functional arylsulfones.

Thiol‐Disulfide Exchange Kinetics and Redox Potential of the Coenzyme M and Coenzyme B Heterodisulfide, an Electron Acceptor Coupled to Energy Conservation in Methanogenic Archaea

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Methanogenic and methanotrophic archaea play important roles in the global carbon cycle by interconverting CO2 and methane. To conserve energy from these metabolic pathways that happen close to the thermodynamic equilibrium, specific electron carriers have evolved to balance the redox potentials between key steps. Reduced ferredoxins required to activate CO2 are provided by energetical coupling to the reduction of the high-potential heterodisulfide (HDS) of coenzyme M (2-mercaptoethanesulfonate) and coenzyme B (7-mercaptoheptanoylthreonine phosphate). While the standard redox potential of this important HDS has been determined previously to be -143 mV (Tietze et al. 2003 DOI:10.1002/cbic.200390053), we have measured thiol disulfide exchange kinetics and reassessed this value by equilibrating thiol-disulfide mixtures of coenzyme M, coenzyme B and mercaptoethanol. We determined the redox potential of the HDS of coenzyme M and coenzyme B to be -16.4 ± 1.7 mV relative to the reference thiol mercaptoethanol (E0’ = -264 mV). The resulting E0’ values are -281 mV for the HDS, -271 mV for the homodisulfide of coenzyme M, and -270 mV for the homodisulfide of coenzyme B. We discuss the importance of these updated values for the physiology of methanogenic and methanotrophic archaea and their implications in terms of energy conservation.

Living Self‐Assembly of Metastable and Stable Two‐Dimensional Platelets from a Single Small Molecule

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This study reports the design of a donor-acceptor (D-A) molecule with two fluorene units on each side of a benzothiadiazole moiety, which allows multiple intermolecular interactions to compete with one another so as to induce the evolution of the metastable 2D platelets to the stable 2D platelets during the self-assembly of the D-A molecule. Importantly, the living seeded self-assembly of metastable and stable 2D structures with precisely controlled sizes can be conveniently achieved using an appropriate supersaturated solution of the D-A molecule as the seeded growth medium that can temporarily hold the almost-proceeding spontaneous nucleation from competing with the seeded growth. The stable 2D platelets with smaller area sizes exhibit higher sensitivity to gaseous dimethyl sulfide, illustrating that the novel living self-assembly method provides more available functional structures with controlled sizes for practical applications. The key finding of this study is that the new living methodology is separated into two independent processes: the elaborate molecular design for various crystalline structures as seeds and the application of an appropriate supersaturated solution as the growth medium to grow the uniform structures with controlled sizes; this would make convenient and possible the living seeded self-assembly of rich 1D, 2D, and 3D architectures.

Total Chemical Synthesis of the SARS‐CoV‐2 Spike Receptor‐Binding Domain

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SARS-CoV-2 and its global spread have created an unprecedented public health crisis. The spike protein of SARS-CoV-2 has gained significant attention due to its crucial role in viral entry into host cells and its potential as both a prophylactic and a target for therapeutic interventions. Herein, we report the first successful total synthesis of the SARS-CoV-2 spike protein receptor binding domain (RBD), highlighting the key challenges and the strategies employed to overcome them. Appropriate utilization of advanced solid phase peptide synthesis and cutting-edge native chemical ligation methods have facilitated the synthesis of the protein molecule. We discuss problems encountered during the chemical synthesis and approaches taken to optimize the yield and the purity of the synthetic protein molecule. Furthermore, we demonstrate that the chemically synthesized spike RBD efficiently binds to the known mini-protein binder LCB1. The successful chemical synthesis of the spike RBD presented here can be utilized to gain valuable insights into SARS-CoV-2 spike RBD biology, advancing our understanding and aiding the development of intervention strategies to combat future coronavirus outbreaks. The modular synthetic approach described in this study can be effectively implemented in the synthesis of other mutated variants or enantiomer of spike RBD for mirror-image drug discovery.

High‐content image‐based screening and deep learning for the detection of anti‐inflammatory drug leads

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We developed a high-content image-based screen that utilizes the pro-inflammatory stimulus lipopolysaccharide (LPS) and murine macrophages (RAW264.7) with the goals of identifying anti-inflammatory drug leads. We screened 2,259 bioactive compounds with annotated mechanisms of action (MOA) to identify compounds that reverse the LPS-induced phenotype in macrophages. We utilized a set of seven fluorescence microscopy probes to generate images that were used to train and optimize a deep neural network classifier to distinguish between unstimulated and LPS-stimulated macrophages. The top hits from the deep learning classifier were validated using a linear classifier trained on individual cells and subsequently investigated in a multiplexed cytokine secretion assay. All 12 hits significantly modulated the expression of at least one cytokine upon LPS stimulation. Seven of these were allosteric inhibitors of the mitogen-activated protein kinase kinase (MEK1/2) and showed distinct effects on cytokine expression, consistent with the complex pharmacology of MEK1/2 inhibition. This deep learning morphological assay identified compounds that modulate the innate immune response to LPS and may aid in identifying new drug leads against sepsis.