A5063718816- Computational Drug Discovery Methods
- Cannabis and Cannabinoid Research
- Pancreatic function and diabetes
- Monoclonal and Polyclonal Antibodies Research
- Glycosylation and Glycoproteins Research
- Neurotransmitter Receptor Influence on Behavior
- Protein Structure and Dynamics
- Microbial Natural Products and Biosynthesis
- Click Chemistry and Applications
- Cell Image Analysis Techniques
- Protein Degradation and Inhibitors
- Pharmacological Receptor Mechanisms and Effects
- Bioinformatics and Genomic Networks
- Machine Learning in Bioinformatics
- RNA and protein synthesis mechanisms
- Biochemical effects in animals
- Enzyme Production and Characterization
- Enzyme Catalysis and Immobilization
- Antimicrobial Peptides and Activities
- Cancer-related gene regulation
- Receptor Mechanisms and Signaling
- Bacterial biofilms and quorum sensing
- Protein Tyrosine Phosphatases
- Diet, Metabolism, and Disease
- Cancer therapeutics and mechanisms
Leiden University
2017-2025
Oncode Institute
2021-2025
Albert Einstein College of Medicine
2024
Centre for Human Drug Research
2024
A clue to a drug's neurotoxicity? The drug BIA 10-2474 inhibits fatty acid amide hydrolase (FAAH), lipase that degrades specific endocannabinoid. On the basis of this activity, was being developed as potential treatment for anxiety and pain. In phase 1 trial drug, one subject died, four others suffered brain damage. As an initial step in investigating whether inhibition off-target proteins by might contribute its clinical neurotoxicity, van Esbroeck et al. used activity-based proteomic...
Abstract Cannabinoid CB 2 receptor (CB R) agonists are investigated as therapeutic agents in the clinic. However, their molecular mode-of-action is not fully understood. Here, we report discovery of LEI-102, a R agonist, used conjunction with three other CBR ligands (APD371, HU308, and CP55,940) to investigate selective activation by binding kinetics, site-directed mutagenesis, cryo-EM studies. We identify key residues for activation. Highly lipophilic HU308 endocannabinoids, but more polar...
Abstract Bacteria have evolved resistance to nearly all known antibacterials, emphasizing the need identify antibiotics that operate via novel mechanisms. Here we report a class of allosteric inhibitors DNA gyrase with antibacterial activity against fluoroquinolone-resistant clinical isolates Escherichia coli . Screening small-molecule library revealed an initial isoquinoline sulfonamide hit, which was optimized medicinal chemistry efforts afford more potent LEI-800. Target identification...
Abstract Computer-Aided Synthesis Planning (CASP) and CASP-based approximated synthesizability scores have rarely been used as generation objectives in Drug Design despite facilitating the in-silico of synthesizable molecules. However, these approaches are disconnected from reality small laboratory drug design, where building block resources limited, thus making notion in-house with already available highly desirable. In this work, we show a successful de novo design workflow generating...
The interpretation of high-dimensional structure–activity data sets in drug discovery to predict ligand–protein interaction landscapes is a challenging task. Here we present Drug Discovery Maps (DDM), machine learning model that maps the activity profile compounds across an entire protein family, as illustrated here for kinase family. DDM based on t-distributed stochastic neighbor embedding (t-SNE) algorithm generate visualization molecular and biological similarity. chemical target space...
Monoacylglycerol lipase (MAGL) regulates endocannabinoid 2-arachidonoylglycerol (2-AG) and eicosanoid signalling. MAGL inhibition provides therapeutic opportunities but clinical potential is limited by central nervous system (CNS)-mediated side effects. Here, we report the discovery of LEI-515, a peripherally restricted, reversible inhibitor, using high throughput screening medicinal chemistry programme. LEI-515 increased 2-AG levels in peripheral organs, not mouse brain. attenuated liver...
Endocannabinoids, an important class of signaling lipids involved in health and disease, are predominantly synthesized metabolized by enzymes the serine hydrolase superfamily. Activity-based protein profiling (ABPP) using fluorescent probes, such as fluorophosphonate (FP)-TAMRA β-lactone-based MB064, enables drug discovery activities for hydrolases. FP-TAMRA MB064 have distinct, albeit partially overlapping, target profiles but cannot be used conjunction due to overlapping...
Phenotypic screening is a powerful approach to identify novel antibiotics, but elucidation of the targets responsible for antimicrobial activity often challenging in case compounds with polypharmacological mode action. Here, we show that activity-based protein profiling maps target interaction landscape series 1,3,4-oxadiazole-3-ones identified phenotypic screen have high antibacterial potency against multidrug-resistant Staphylococcus aureus. In situ competitive and comparative chemical...
During infection, the human opportunistic pathogen Pseudomonas aeruginosa forms protective biofilms, whose matrix consists of proteins, nucleic acids, and polysaccharides such as alginate, Psl, Pel. a polymeric pentasaccharide composed mannose, rhamnose, glucose, is produced during early stages biofilm formation, serving barrier against antibiotics immune system. The Psl biosynthesis gene cluster, besides encoding various glycosyltransferases, also includes an endoglycosidase, PslG. Here, we...
The human genome encodes 518 protein kinases that are pivotal for drug discovery in various therapeutic areas such as cancer and autoimmune disorders. majority of kinase inhibitors target the conserved ATP-binding pocket, making it difficult to develop selective inhibitors. To characterize prioritize kinase-inhibiting candidates, efficient methods desired determine engagement across cellular kinome. In this study, we present CellEKT (Cellular Endogenous Kinase Targeting), an optimized robust...
ADVERTISEMENT RETURN TO ISSUEPREVAddition/CorrectionNEXTORIGINAL ARTICLEThis notice is a correctionABHD2 Inhibitor Identified by Activity-Based Protein Profiling Reduces Acrosome ReactionMarc P. Baggelaar*Marc BaggelaarDepartment of Molecular Physiology, Leiden University, Einsteinweg 55, 2333 CC Leiden, The Netherlands*E-mail: [email protected]More Marc Baggelaarhttp://orcid.org/0000-0002-9784-6250, Hans den DulkHans DulkDepartment NetherlandsMore Dulk, Bogdan I. FloreaBogdan...
Molecules generated by Computer-Aided Drug Design often lack synthesizability to be valuable because Synthesis Planning (CASP) and CASP-based approximated scores have rarely been used as generation objectives, despite facilitating the in-silico of synthesizable molecules. Published approximate a general notion with nearly unlimited building block resources. However, this approach is disconnected from reality small laboratory drug design, where resources are limited, making in-house that uses...
ABHD2 is a serine hydrolase that belongs to the subgroup of α,β-hydrolase fold-containing proteins, which involved in virus propagation, immune response, and fertilization. Chemical tools selectively modulate activity an acute setting are highly desired investigate its biological role, but currently lacking. Here, we report library-versus-library screening using activity-based protein profiling (ABPP) evaluate parallel selectivity focused lipase inhibitor library against panel closely...
Diacylglycerol lipases (DAGL) are responsible for the biosynthesis of endocannabinoid 2-arachidonoylglycerol. The fluorescent activity-based probes DH379 and HT-01 have been previously shown to label DAGLs cross-react with serine hydrolase ABHD6. Here, we report synthesis characterization two new quenched 1 2, design which was based on structures HT-01, respectively. Probe contains a BODIPY-FL 2,4-dinitroaniline moiety as fluorophore-quencher pair, whereas probe 2 employs Cy5-fluorophore...
Drug discovery programs of covalent irreversible, mechanism-based enzyme inhibitors often focus on optimization potency as determined by IC50-values in biochemical assays. These assays do not allow the characterization binding activity (Ki) and reactivity (kinact) individual kinetic parameters inhibitors. Here, we report development a substrate assay to study influence acidity (pKa) heterocyclic leaving group triazole urea derivatives diacylglycerol lipase (DAGL)-α Surprisingly, found that...
Abstract The cannabinoid receptor type 2 (CB R) is a G protein‐coupled with therapeutic potential for the treatment of inflammatory disorders. Fluorescent probes are desirable to study its localization, expression and occupancy. Previously, we have reported photoaffinity probe LEI‐121 that stabilized inactive conformation CB R. Here, report structure‐based design novel bifunctional captures active R upon irradiation light. An alkyne handle was incorporated visualize using click‐chemistry...
Kinase inhibitors are an important class of anti-cancer drugs, with 80 clinically approved, and >100 in active clinical testing. Most bind competitively the ATP-binding site, leading to challenges selectivity for a specific kinase, resulting risks toxicity general off-target effects. Assessing binding inhibitor entire kinome is experimentally possible but expensive. A reliable interpretable computational prediction kinase would greatly benefit discovery optimisation process. Here, we use...
The integration of diverse chemical tools like small-molecule inhibitors, activity-based probes (ABPs), and proteolysis targeting chimeras (PROTACs) advances clinical drug discovery facilitates the exploration various biological facets targeted proteins. Here, we report development such a toolbox for human Parkinson disease protein 7 (PARK7/DJ-1) implicated in Parkinson's cancers. By combining structure-guided design, miniaturized library synthesis, high-throughput screening, identified two...
The human genome encodes 518 protein kinases that are pivotal for drug discovery in various therapeutic areas such as cancer and autoimmune disorders. majority of kinase inhibitors target the conserved ATP-binding pocket, making it difficult to develop selective inhibitors. To characterize prioritize kinase-inhibiting candidates, efficient methods desired determine engagement across cellular kinome. In this study, we present CellEKT (Cellular Endogenous Kinase Targeting), an optimized robust...
Recent advancements in deep learning and generative models have significantly expanded the applications of virtual screening for drug-like compounds. Here, we introduce a multitarget transformer model,
A set of mannuronic-acid-based iminosugars, consisting the C-5-carboxylic acid, methyl ester and amide analogues 1deoxymannorjirimicin (DMJ), was synthesised their pH-dependent conformational behaviour studied. Under acidic conditions carboxylic acid adopted an "inverted" 1 C4 chair conformation as opposed to "normal" 4 C1 at basic pH. This change is explained in terms stereoelectronic effects ring substituents it parallels mannuronic oxocarbenium ion. Because this solution-phase behaviour,...
Diacylglycerol lipases (DAGL) produce the endocannabinoid 2-arachidonoylglycerol, a key modulator of neurotransmitter release. Chemical tools that visualize endogenous DAGL activity are desired. Here, we report design, synthesis and application triazole urea probe for equipped with norbornene as biorthogonal handle. The selectivity was assessed activity-based protein profiling. This potent against DAGLα (IC50 = 5 nM) it successfully applied two-step labeling using an inverse electron-demand...
Proteolysis is fundamental to many biological processes. In the immune system, it underpins activation of adaptive response: degradation antigenic material into short peptides and presentation thereof on major histocompatibility complexes, leads T-cells. This initiates response against pathogens. Studying proteolysis difficult, as oft-used polypeptide reporters are susceptible proteolytic sequestration themselves. Here we present a new approach that allows imaging antigen throughout...