A5036784729- Computational Drug Discovery Methods
- RNA and protein synthesis mechanisms
- Biochemical and Molecular Research
- Enzyme Structure and Function
- RNA modifications and cancer
- Microbial Natural Products and Biosynthesis
- Trypanosoma species research and implications
- Research on Leishmaniasis Studies
- Protein Structure and Dynamics
- Chemical Synthesis and Analysis
- Antibiotic Resistance in Bacteria
- Synthesis and Characterization of Heterocyclic Compounds
- Crystallization and Solubility Studies
- Quinazolinone synthesis and applications
- Peptidase Inhibition and Analysis
- Carbohydrate Chemistry and Synthesis
- Metabolomics and Mass Spectrometry Studies
- Analytical Chemistry and Chromatography
- Synthesis and Biological Evaluation
- Glycosylation and Glycoproteins Research
- Protein Kinase Regulation and GTPase Signaling
- Enzyme function and inhibition
- Bacteriophages and microbial interactions
- ATP Synthase and ATPases Research
- Electrochemical sensors and biosensors
University of Bergen
2015-2025
Fraunhofer Institute for Translational Medicine and Pharmacology
2024
Merck (Germany)
2024
University of Girona
2024
Instruct-ERIC
2024
University of Dundee
2008-2018
Wellcome Centre for Anti-Infectives Research
2018
Johannes Gutenberg University Mainz
2013-2015
Philipps University of Marburg
2002-2009
University of California, San Francisco
2005-2006
To enable the establishment of a drug discovery operation for neglected diseases, out 2.3 million commercially available compounds 222 552 were selected an in silico library, 57 438 diverse general screening and 1 697 focused kinase set. Compiling these libraries required robust strategy compound selection. Rules unwanted groups defined selection criteria to enrich lead-like which facilitate straightforward structure-activity relationship exploration established. Further, literature patent...
N-Myristoyltransferase (NMT) represents a promising drug target for human African trypanosomiasis (HAT), which is caused by the parasitic protozoa Trypanosoma brucei. We report optimization of high throughput screening hit (1) to give lead molecule DDD85646 (63), has potent activity against enzyme (IC50 = 2 nM) and T. brucei (EC50 in culture. The compound good oral pharmacokinetics cures rodent models peripheral HAT infection. This provides an excellent tool validation NMT as well valuable...
The increasing number of RNA crystal structures enables a structure-based approach to the discovery new RNA-binding ligands. To develop poorly explored area RNA-ligand docking, we have conducted virtual screening exercise for purine riboswitch probe strengths and weaknesses docking. Using standard protein-ligand docking program with only minor modifications, four ligands binding affinities in micromolar range were identified, including two compounds based on molecular scaffolds not...
The enzyme pteridine reductase 1 (PTR1) is a potential target for new compounds to treat human African trypanosomiasis. A virtual screening campaign fragments inhibiting PTR1 was carried out. Two novel chemical series were identified containing aminobenzothiazole and aminobenzimidazole scaffolds, respectively. One of the hits (2-amino-6-chloro-benzimidazole) subjected crystal structure analysis high resolution in complex with obtained, confirming predicted binding mode. However, structures...
Judging if a protein is able to bind orally available molecules with high affinity, i.e. druggable, an important step in target assessment. In order derive structure-based method predict druggability, comprehensive, nonredundant data set containing crystal structures of 71 druggable and 44 less proteins was compiled by literature search mining. This subsequently used train druggability predictor (DrugPred) using partial least-squares projection latent discriminant analysis (PLS-DA). DrugPred...
Molecular docking is widely used to predict novel lead compounds for drug discovery. Success depends on the quality of scoring function, among other factors. An imperfect function can mislead by predicting incorrect ligand geometries or selecting nonbinding molecules over true ligands. These false-positive hits may be considered "decoys". Although these decoys are frustrating, they potentially provide important tests a algorithm; more subtle decoy, rigorous test. Indeed, decoy databases have...
Eubacterial tRNA-guanine transglycosylase (TGT) is involved in the hypermodification of cognate tRNAs, leading to exchange G34 by preQ1 at wobble position anticodon loop. Mutation tgt gene Shigella flexneri results a significant loss pathogenicity bacterium due inefficient translation virulence protein mRNA. Herein, we describe discovery ligand with an unexpected binding mode. On basis this mode, three slightly deviating pharmacophore hypotheses have been derived. Virtual screening based on...
The new analogue 2 of combretastatin A-4 was discovered to be an inhibitor tubulin polymerization with IC50 7.6 μM and reduced angiogenesis in the vivo chick embryo model. Interestingly, a series 2,3-diarylmaleimides closely related this lead, no other compound found active assay. However, by screening assay 10 identified as potent indicating alternative target. Indeed, molecular modeling studies suggest reasonable binding mode at ATP-binding site model kinase CDK2. Motivated these results,...
Trypanosoma brucei N-myristoyltransferase (TbNMT) is an attractive therapeutic target for the treatment of human African trypanosomiasis (HAT). From previous studies, we identified pyrazole sulfonamide, DDD85646 (1), a potent inhibitor TbNMT. Although this compound represents excellent lead, poor central nervous system (CNS) exposure restricts its use to hemolymphatic form (stage 1) disease. With clear clinical need new drug treatments HAT that address both and CNS stages disease, chemistry...
The process by which researchers from all over the world can apply for projects using EFSL poised to ECBL at EU-OPENSCREEN screening facilities and optimize hits identified through our network of chemistry partners.
Protein kinases constitute an attractive family of enzyme targets with high relevance to cell and disease biology. Small molecule inhibitors are powerful tools dissect elucidate the function in chemical biology research serve as potential starting points for drug discovery. However, discovery development novel remains challenging. Here, we describe a structure-based de novo design approach that generates novel, hinge-binding fragments synthetically feasible can be elaborated small libraries....
Glucose-1-phosphate thymidylyltransferase (RmlA) catalyzes the condensation of glucose-1-phosphate (G1P) with deoxy-thymidine triphosphate (dTTP) to yield dTDP-d-glucose and pyrophosphate. This is first step in l-rhamnose biosynthetic pathway. l-Rhamnose an important component cell wall many microorganisms, including Mycobacterium tuberculosis Pseudomonas aeruginosa. Here we describe nanomolar inhibitors P. aeruginosa RmlA. These thymine analogues were identified by high-throughput screening...
Crystallography has guided the hybridization of two series Trypanosoma brucei N-myristoyltransferase (NMT) inhibitors, leading to a novel highly selective series. The effect combining selectivity enhancing elements from pharmacophores is shown be additive and led compounds that have greater than 1000-fold for TbNMT vs HsNMT. Further optimization hybrid identified with significant trypanocidal activity capable crossing blood-brain barrier. By using CF-1 mdr1a deficient mice, we were able...
Abstract New drugs are urgently needed for the treatment of tropical parasitic diseases such as leishmaniasis and human African trypanosomiasis (HAT). This work involved a high‐throughput screen focussed kinase set ∼3400 compounds to identify potent parasite‐selective inhibitors an enzymatic Leishmania CRK3–cyclin 6 complex. The aim this study is provide chemical validation that CRK3–CYC6 drug target. Eight hit series were identified, which four followed up. optimisation these using...
The ChEMBL database was mined to efficiently assemble an ion channel-focused screening library. compiled library consists of 3241 compounds representing 123 templates across nine channel categories. Compounds in the are annotated with their respective category facilitate back-tracing prospective molecular targets from phenotypic results. established workflow is adaptable construction focused libraries for other therapeutic target classes diverse recognition motifs.
Abstract Genetic studies indicate that the enzyme pteridine reductase 1 (PTR1) is essential for survival of protozoan parasite Trypanosoma brucei . Herein, we describe development and optimisation a novel series PTR1 inhibitors, based on benzo[ d ]imidazol‐2‐amine derivatives. Data are reported 33 compounds. This was initially discovered by virtual screening campaign ( J. Med. Chem ., 2009 , 52 4454). The inhibitors adopted an alternative binding mode to those natural ligands, biopterin...
Fatty acid biosynthesis is an essential component of metabolism in both eukaryotes and prokaryotes. The fatty biosynthetic pathway Gram-negative bacteria established therapeutic target. Two homologous enzymes FabA FabZ catalyze a key step biosynthesis; dehydrate hydroxyacyl acids that are coupled via phosphopantetheine to acyl carrier protein (ACP). resulting trans-2-enoyl-ACP further polymerized processive manner. FabA, however, carries out second reaction involving isomerization...