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Open AccessArticle

Design of a Novel and Selective IRAK4 Inhibitor Using Topological Water Network Analysis and Molecular Modeling Approaches

1
Graduate School of New Drug Discovery and Development, Chungnam National University, 99 Daehak-ro, Yuseong-gu, Daejeon 34134, Korea
2
College of Pharmacy, Keimyung University, 1095 Dalgubeol-daero, Dalseo-Gu, Daegu 42601, Korea
*
Author to whom correspondence should be addressed.
Molecules 2018, 23(12), 3136; https://doi.org/10.3390/molecules23123136
Received: 7 November 2018 / Revised: 28 November 2018 / Accepted: 28 November 2018 / Published: 29 November 2018
(This article belongs to the Special Issue Application of Computational Methods in Drug Design)
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. View Full-Text
Keywords: Topological water network; kinase selectivity; IRAK4; pharmacophore mapping; virtual screening; molecular docking; molecular dynamics simulation Topological water network; kinase selectivity; IRAK4; pharmacophore mapping; virtual screening; molecular docking; molecular dynamics simulation
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MDPI and ACS Style

Lee, M.H.; Balupuri, A.; Jung, Y.-R.; Choi, S.; Lee, A.; Cho, Y.S.; Kang, N.S. Design of a Novel and Selective IRAK4 Inhibitor Using Topological Water Network Analysis and Molecular Modeling Approaches. Molecules 2018, 23, 3136.

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