Publications by authors named "H W T van Vlijmen"
Article Synopsis
- Despite existing medicines for preventing RSV, there’s a need for effective post-exposure treatments.
- Research led to the development of new derivatives of JNJ-8003, a promising non-nucleoside polymerase inhibitor for RSV with strong antiviral activity.
- Structural modifications, including bioisosteric replacement with triazole, have maintained effectiveness while enhancing diversity and allowing further adjustments in the drug design.
Article Synopsis
- PROTACs are advanced tools in drug development that enable targeted protein degradation by utilizing a ligand for the target protein, a ligand for E3 ligase, and a connecting linker.
- Despite over 600 known E3 ligases, only a few are used in therapeutic applications due to limited available ligands and structural data complicating ligand design.
- This study aims to identify promising E3 ligases for development by using chemoproteomic data and AlphaFold models to evaluate ligandability, focusing on potentially reactive cysteines to enhance the PROTAC arsenal.
The European Lead Factory (ELF) is a consortium of universities and small and medium-sized enterprises (SMEs) dedicated to drug discovery, and the pharmaceutical industry. This unprecedented consortium provides high-throughput screening, triage, and hit validation, including to non-consortium members. The ELF library was created through a novel compound-sharing model between nine pharmaceutical companies and expanded through library synthesis by chemistry-specialized SMEs.
View Article and Find Full Text PDFMembrane proteins have diverse functions within cells and are well-established drug targets. The advances in membrane protein structural biology have revealed drug and lipid binding sites on membrane proteins, while computational methods such as molecular simulations can resolve the thermodynamic basis of these interactions. Particularly, alchemical free energy calculations have shown promise in the calculation of reliable and reproducible binding free energies of protein-ligand and protein-lipid complexes in membrane-associated systems.
View Article and Find Full Text PDFArticle Synopsis
- - The respiratory syncytial virus (RSV) polymerase complex, made up of proteins L and P, is essential for RNA transcription and modification, but details on how inhibitors interact with it have been unclear.
- - A new non-nucleoside inhibitor, JNJ-8003, demonstrates strong antiviral activity and effectively inhibits the polymerase complex, with structural analysis showing how it tightly binds to a specific site on the capping domain.
- - JNJ-8003 disrupts early stages of RNA synthesis, revealing potential for developing broad-spectrum antiviral treatments based on its molecular interactions with the viral polymerase machinery.