ArticleMolecules (Basel, Switzerland)2018
Design of a Novel and Selective IRAK4 Inhibitor Using Topological Water Network Analysis and Molecular Modeling Approaches.
Article in Molecules (Basel, Switzerland), 2018. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 8 papers.
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Who cites it
8 citing papers in PubMed, 11 citations in OpenAlex.
- Unraveling Extremely DamagingJournal of personalized medicine · 2023Article
- TWN-RENCOD: A novel method for protein binding site comparison.Computational and structural biotechnology journal · 2023Article
- TWN-FS method: A novel fragment screening method for drug discovery.Computational and structural biotechnology journal · 2023Article
- Drug Repositioning Applied to Cardiovascular Disease in Mucopolysaccharidosis.Life (Basel, Switzerland) · 2022Article
- Small Molecule Inhibitors of DYRK1A Identified by Computational and Experimental Approaches.International journal of molecular sciences · 2020Article
- A highly selective inhibitor of interleukin-1 receptor-associated kinases 1/4 (IRAK-1/4) delineates the distinct signaling roles of IRAK-1/4 and the TAK1 kinase.The Journal of biological chemistry · 2020Article
- Pharmacophoric Site Identification and Inhibitor Design for Autotaxin.Molecules (Basel, Switzerland) · 2019Article
- Topological Water Network Analysis Around Amino Acids.Molecules (Basel, Switzerland) · 2019Article
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Authors and funding
7 authors at 2 institutions in 1 country.
Funding
Abstract
Protein kinases are deeply involved in immune-related diseases and various cancers. They are a potential target for structure-based drug discovery, since the general structure and characteristics of kinase domains are relatively well-known. However, the ATP binding sites in protein kinases, which serve as target sites, are highly conserved, and thus it is difficult to develop selective kinase inhibitors. To resolve this problem, we performed molecular dynamics simulations on 26 kinases in the aqueous solution, and analyzed topological water networks (TWNs) in their ATP binding sites. Repositioning of a known kinase inhibitor in the ATP binding sites of kinases that exhibited a TWN similar to interleukin-1 receptor-associated kinase 4 (IRAK4) allowed us to identify a hit molecule. Another hit molecule was obtained from a commercial chemical library using pharmacophore-based virtual screening and molecular docking approaches. Pharmacophoric features of the hit molecules were hybridized to design a novel compound that inhibited IRAK4 at low nanomolar levels in the in vitro assay.
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