A5074083544- Computational Drug Discovery Methods
- Crystallization and Solubility Studies
- X-ray Diffraction in Crystallography
- Receptor Mechanisms and Signaling
- Protein Structure and Dynamics
- Pharmacogenetics and Drug Metabolism
- Microtubule and mitosis dynamics
- Cannabis and Cannabinoid Research
- Analytical Chemistry and Chromatography
- Chemical Synthesis and Analysis
- Drug Transport and Resistance Mechanisms
- Sirtuins and Resveratrol in Medicine
- Estrogen and related hormone effects
- Synthesis and biological activity
- Click Chemistry and Applications
- DNA and Nucleic Acid Chemistry
- HIV/AIDS drug development and treatment
- SARS-CoV-2 and COVID-19 Research
- Pharmacological Receptor Mechanisms and Effects
- Microbial Natural Products and Biosynthesis
- Protein Kinase Regulation and GTPase Signaling
- Ubiquitin and proteasome pathways
- Cancer therapeutics and mechanisms
- Calcium signaling and nucleotide metabolism
- Drug Solubulity and Delivery Systems
University of Eastern Finland
2016-2025
University of Tübingen
2016-2025
Finland University
2014-2025
German Center for Infection Research
2025
University Children's Hospital Tübingen
2016-2024
Bernstein Center for Computational Neuroscience Tübingen
2022-2024
University of Helsinki
2009-2024
Universitätsklinikum Tübingen
2023
German Cancer Research Center
2021
Heidelberg University
2021
In 1982, Kuntz et al. published an article with the title "A Geometric Approach to Macromolecule-Ligand Interactions", where they described a method "to explore geometrically feasible alignment of ligands and receptors known structure". Since then, small molecule docking has been employed as fast way estimate binding pose given compound within specific target protein also predict affinity. Remarkably, first suggested by colleagues aimed poses but very little was specified about This raises...
Abstract Motivation An essential part of drug discovery is the accurate prediction binding affinity new compound–protein pairs. Most standard computational methods assume that compounds or proteins test data are observed during training phase. However, in real-world situations, and sampled from different domains with distributions. To cope this challenge, we propose a deep learning-based approach consists three steps. In first step, encoder network learns novel representation proteins. end,...
Diminished hepatocyte regeneration is a key feature of acute and chronic liver diseases after extended resections, resulting in the inability to maintain or restore sufficient functional mass. Therapies are lacking, making transplantation only curative option for end-stage disease. Here, we report on structure-based development characterization (nuclear magnetic resonance [NMR] spectroscopy) first-in-class small molecule inhibitors dual-specificity kinase MKK4 (MKK4i). MKK4i increased upon...
Abstract Fatty acids are a primary source of carbon for Pseudomonas aeruginosa (PA) in the airways people with cystic fibrosis (CF). Here, we use tandem mass-tag proteomics to analyse protein expression profile CF clinical isolate grown on different fatty acids. Two acyl-CoA dehydrogenases (designated FadE1 and FadE2) strongly induced during growth displays strong preference long-chain acyl-CoAs, whereas FadE2 exclusively utilizes medium-chain acyl-CoAs. Structural analysis enzymes enables...
With data from recent large-scale drug sensitivity measurement campaigns, it is now possible to build and test models predicting responses for more than one hundred anticancer drugs against several hundreds of human cancer cell lines. Traditional quantitative structure–activity relationship (QSAR) approaches focus on small molecules in searching their structural properties predictive the biological activity a single line or tissue type. We extend this research two directions: (1) an...
Treatment options for COVID-19, caused by SARS-CoV-2, remain limited. Understanding viral pathogenesis at the molecular level is critical to develop effective therapy. Some recent studies have explored SARS-CoV-2-host interactomes and provided great resources understanding replication. However, host proteins that functionally associate with SARS-CoV-2 are localized in corresponding subnetwork within comprehensive human interactome. Therefore, constructing a downstream network including all...
The main protease (Mpro, 3CLpro) of SARS-CoV-2 is an attractive target in coronaviruses because its crucial involvement viral replication and transcription. Here, we report on the design, synthesis, structure-activity relationships novel small-molecule thioesters as Mpro inhibitors. Compounds 3w 3x exhibited excellent inhibition with kinac/Ki 58,700 M-1 s-1 (Ki = 0.0141 μM) 27,200 0.0332 μM), respectively. In Calu-3 Vero76 cells, compounds 3h, 3i, 3l, 3r, 3v, 3w, displayed antiviral activity...
The Kelch-like ECH-associated protein 1 (KEAP1) - Nuclear factor erythroid 2 -related (NRF2) pathway is the major transcriptional stress response system in cells against oxidative and electrophilic stress. NRF2 frequently constitutively active many cancers, rendering resistant to chemo- radiotherapy. Loss-of-function (LOF) mutations repressor KEAP1 are common non-small cell lung cancer, particularly adenocarcinoma. While can occur throughout gene, they enriched certain areas, indicating that...
Abstract Bivalent molecules consisting of groups connected through bridging linkers often exhibit strong target binding and unique biological effects. However, developing bivalent inhibitors with the desired activity is challenging due to dual motif architecture these variability that can be introduced differing linker structures geometries. We report a set alternatively linked EGFR simultaneously occupy ATP substrate allosteric pockets. Crystal show initial redesigned trisubstituted...
Abstract Fibroblast growth factor receptor (FGFR)−2 can be inhibited by FGFR-selective or non-selective tyrosine kinase inhibitors (TKIs). Selective TKIs are approved for cholangiocarcinoma (CCA) with FGFR2 fusions; however, their application is limited a characteristic pattern of adverse events evocation domain mutations. A comprehensive characterization patient cohort treated the TKI lenvatinib reveals promising efficacy in FGFR2-driven CCA. In bed-to-bench approach, we investigate fusion...
Chemical changes performed on 1a (sirtinol) led to a series of SIRT1/2 inhibitors, in some cases more potent than mainly against SIRT1. Tested human leukemia U937 cells, the benzamide and anilide derivatives 1b, 1c, 2b, 2c as well 4-(2-phenylpropyl)thioanalogue 4c showed huge apoptosis induction, while sulfinyl sulfonyl (5b, 5c, 6a-c) were highly efficient granulocytic differentiation. When assayed MOLT4 breast MDA-MB-231 colon RKO cancer cell lines, 2b (salermide) phenylpropylthio analogue...
A mutated KRAS protein is frequently observed in human cancers. Traditionally, the oncogenic properties of missense mutants at position 12 (G12X) have been considered as equal. Here, by assessing probabilities occurrence all G12X mutations and dynamics we show that this assumption does not hold true. Instead, our findings revealed an outstanding mutational bias. We conducted a thorough analysis assessed to what extent mutation frequencies follow random distribution. Unique tissue-specific...
The worldwide COVID-19 pandemic caused by the coronavirus SARS-CoV-2 urgently demands novel direct antiviral treatments. main protease (Mpro) and papain-like (PLpro) are attractive drug targets among coronaviruses due to their essential role in processing polyproteins translated from viral RNA. In this study, we virtually screened 688 naphthoquinoidal compounds derivatives against Mpro of SARS-CoV-2. Twenty-four were selected evaluated biochemical assays using a fluorogenic substrate....
The emergence of ultra-large screening libraries, filled to the brim with billions readily available compounds, poses a growing challenge for docking-based virtual screening. Machine learning (ML)-boosted strategies like tool HASTEN combine rapid ML prediction brute-force docking small fractions such libraries increase throughput and take on giga-scale libraries. In our case study an anti-bacterial chaperone anti-viral kinase, we first generated baseline 1.56 billion compounds in Enamine...
Type 2 human sirtuin (SIRT2) is a NAD+-dependent cytoplasmic protein that colocalized with HDAC6 on microtubules. SIRT2 has been shown to deacetylate α-tubulin and control mitotic exit in the cell cycle. To date, some small molecular inhibitors of have identified; however, more are still needed improve understanding biological function discover its possible therapeutic indications. In this paper, an silico identification procedure described for discovering novel inhibitors. Molecular...
In the present study, identification of chiral 1,3,4-oxadiazol-2-ones as potent and selective FAAH inhibitors has been described. The separated enantiomers showed clear differences in potency selectivity toward both MAGL. Additionally, importance chirality on inhibitory activity was proven by simplification approach removing a methyl group at 3-position 1,3,4-oxadiazol-2-one ring. most compound series, S-enantiomer 3-(1-(4-isobutylphenyl)ethyl)-5-methoxy-1,3,4-oxadiazol-2(3H)-one (JZP-327A,...
Abstract L ‐Type amino acid transporter 1 (LAT1) is a transmembrane protein expressed abundantly at the blood–brain barrier (BBB), where it ensures transport of hydrophobic acids from blood to brain. Due its unique substrate specificity and high expression BBB, LAT1 an intriguing target for carrier‐mediated drugs into In this study, comparative molecular field analysis (CoMFA) model with considerable statistical quality ( Q 2 =0.53, R =0.75, SE=0.77, SE=0.57) good external predictivity CCC...
Transcription factors are pivotal regulators of gene transcription, and many diseases associated with the deregulation transcriptional networks. In heart, transcription GATA4 NKX2-5 required for cardiogenesis. interact physically, activation GATA4, in cooperation NKX2-5, is essential stretch-induced cardiomyocyte hypertrophy. Here, we report identification four small molecule families that either inhibit or enhance GATA4–NKX2-5 synergy. A fragment-based screening, reporter assay,...
Abstract Structure‐based virtual screening using a D 2 receptor homology model was performed to identify dopamine ligands as potential antipsychotics. From library of 6.5 million compounds, 21 were selected and subjected experimental validation. these compounds tested, ten identified (47.6 % success rate, among them antagonists, expected) that have additional affinity for other receptors in particular 5‐HT 2A receptors. The ( K i values) the ranged from 58 n m about 24 μ . Similarity...