A5075997652- Cancer Immunotherapy and Biomarkers
- Synthesis and Biological Evaluation
- Ubiquitin and proteasome pathways
- CAR-T cell therapy research
- Click Chemistry and Applications
- Protein Degradation and Inhibitors
- Carbohydrate Chemistry and Synthesis
- Synthesis of Organic Compounds
- Cancer, Hypoxia, and Metabolism
- Peptidase Inhibition and Analysis
- Computational Drug Discovery Methods
- Synthesis and biological activity
- Immune Cell Function and Interaction
- Antimicrobial Resistance in Staphylococcus
- Machine Learning in Materials Science
- Biochemical and Structural Characterization
- Advanced Electron Microscopy Techniques and Applications
- Advanced Polymer Synthesis and Characterization
- Biotin and Related Studies
- Glycosylation and Glycoproteins Research
- Cancer, Stress, Anesthesia, and Immune Response
- Lung Cancer Research Studies
- Bacterial Genetics and Biotechnology
- Colorectal Cancer Treatments and Studies
- Pharmacological Receptor Mechanisms and Effects
Jagiellonian University
2015-2024
Silesian University of Technology
2013-2018
Large language models have greatly enhanced our ability to understand biology and chemistry, yet robust methods for structure-based drug discovery, quantum chemistry structural are still sparse. Precise biomolecule-ligand interaction datasets urgently needed large models. To address this, we present MISATO, a dataset that combines mechanical properties of small molecules associated molecular dynamics simulations ~20,000 experimental protein-ligand complexes with extensive validation data....
We describe a new class of potent PD-L1/PD-1 inhibitors based on terphenyl scaffold that is derived from the rigidified biphenyl-inspired structure. Using in silico docking, we designed and then experimentally demonstrated effectiveness terphenyl-based scaffolds inhibiting PD-1/PD-L1 complex formation using various biophysical biochemical techniques. also present high-resolution structure PD-L1 with one our most to identify key PD-L1/inhibitor interactions at molecular level. In addition,...
The PD-1/PD-L1 axis has proven to be a highly efficacious target for cancer immune checkpoint therapy with several approved antibodies. Also, small molecules based on biphenyl core can antagonize PD-1/PD-L1, leading the in vitro formation of PD-L1 dimers. However, their development remains challenging, as we do not yet fully understand mode action. In this work, designed new scaffold our previously solved high-resolution structures low-molecular-weight inhibitors bound PD-L1. A compound...
Targeting the programmed cell death protein 1/programmed 1 ligand (PD-1/PD-L1) interaction has become an established strategy for cancer immunotherapy. Although hundreds of small-molecule, peptide, and peptidomimetic inhibitors have been proposed in recent years, only a limited number drug candidates show good PD-1/PD-L1 blocking activity cell-based assays. In this article, we compare representative molecules from different classes terms their dissociation capacity measured by HTRF vitro...
Development of small molecules targeting the PD-L1/PD-1 interface is advancing both in industry and academia, but only a few have reached early-stage clinical trials. Here, we take closer look at general druggability PD-L1 using silico hot spot mapping nuclear magnetic resonance (NMR)-based characterization. We found that conformational elasticity surface strongly influences formation spots. deconstructed several generations known inhibitors into fragments examined their binding properties...
Hexokinase 2 (HK2), an enzyme of the sugar kinase family, plays a dual role in glucose metabolism and mediating cancer cell apoptosis, making it attractive target for therapy. While positive HK2 expression usually promotes cells survival, silencing or inhibiting this has been found to improve effectiveness anti-cancer drugs even result death. Previously, benitrobenrazide (BNBZ) was characterized as potent inhibitor with good activity mice, but effect its trihydroxy moiety (pyrogallol-like)...
The pharmacological effects of carbon to silicon bioisosteric replacements have been widely explored in drug design and medicinal chemistry. Here, we present a systematic investigation the impact different silyl groups on anticancer activity mucobromic acid (MBA) bearing furan-2(5H)-one core. We describe comprehensive characterization obtained compounds with respect their potency selectivity towards cancer cells. All four novel exert stronger antiproliferative than MBA. Moreover, 3b induce...
Accumulating evidence suggests that six proteases encoded in the spl operon of a dangerous human pathogen, Staphylococcus aureus, may play role virulence. Interestingly, SplA, B, D, and E have complementary substrate specificities while SplF remains to be characterized this regard. Here, we describe prerequisites heterologous expression system for active protease characterize enzyme terms specificity its structural determinants. Substrate is comprehensively profiled using combinatorial...
A series of glycoconjugates, derivatives genistein containing a C-glycosylated carbohydrate moiety, were synthesized and their anticancer activity was tested in vitro the human cell lines HCT 116 DU 145. The target compounds 15–17 by treating ω-bromoalkyl C-glycosides derived from L-rhamnal (1) with tetrabutylammonium salt genistein. new, metabolically stable analogs previously studied O-glycosidic inhibited proliferation cancer through inhibition cycle.
Abstract Nutlin‐3a is a reversible inhibitor of the p53/MDM2 interaction. We have synthesized derivative Nutlin‐3a‐aa bearing an additional exocyclic methylene group in piperazinone moiety. more active than against purified wild‐type MDM2, and effective at increasing p53 levels releasing transcription target genes from MDM2‐induced repression. X‐ray analysis MDM2‐bound indicated that orientation its modified ring was altered comparison to Nutlin‐3a, with pointing away protein surface. Our...
Therapeutic antibodies directed against either programmed cell death-1 protein (PD-1) or its ligand PD-L1 have demonstrated efficacy in the treatment of various cancers. In contrast with antibodies, small molecules potential for increased tissue penetration; better pharmacology; and therefore, improved antitumor activity. A series nonsymmetric C2 inhibitors were synthesized evaluated PD-1/PD-L1 interaction inhibition. These compounds induced dimerization effectively blocked PD-L1/PD-1 a...
Protein assembly plays an important role throughout all phyla of life, both physiologically and pathologically. In particular, aggregation polymerization proteins are key-strategies that regulate cellular function. recent years, methods to experimentally study the process on a single-molecule level have been developed. This progress concomitantly has triggered question how analyze this type single-filament data adequately what experimental conditions necessary allow meaningful interpretation...
By binding to the spliceosomal protein Snu66, human ubiquitin-like Hub1 is a modulator of spliceosome performance and facilitates alternative splicing. Small molecules that bind would be interest study protein-protein interaction Hub1/Snu66, which linked several pathologies, such as hypercholesterolemia, premature aging, neurodegenerative diseases, cancer. To identify small molecule ligands for Hub1, we used interface analysis, peptide modeling Hub1/Snu66 fragment-based NMR screening....
Here, we report the fragment-based drug discovery of potent and selective fragments that disrupt Spire2–FMN2 but not Spire1–FMN2 interaction. Hit were identified in a differential scanning fluorimetry-based screen an in-house library 755 compounds subsequently validated multiple orthogonal biophysical assays, including fluorescence polarization, microscale thermophoresis, 1H–15N HSQC nuclear magnetic resonance. Extensive structure–activity relationships combined with molecular docking...
Here, we report a novel class of potent PD-L1/PD-1 inhibitors based on the rigidified biphenyl-inspired structure – terphenyls. Using in-silico docking, designed and later experimentally shown efficacy terphenyl-based scaffolds to inhibit PD-1/PD-L1 complex formation using various biophysical biochemical techniques. We also high-resolution PD-L1 with our most allowing identification key interactions at molecular level. Moreover, show activating antitumor response primary T-cells derived from...
<p>Here, we report a novel class of potent PD-L1/PD-1 inhibitors based on the rigidified biphenyl-inspired structure – terphenyls. Using in-silico docking, designed and later experimentally shown efficacy terphenyl-based scaffolds to inhibit PD-1/PD-L1 complex formation using various biophysical biochemical techniques. We also high-resolution PD-L1 with our most allowing identification key interactions at molecular level. Moreover, show activating antitumor response primary T-cells...