Cargando…

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

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 se...

Descripción completa

Detalles Bibliográficos
Autores principales: Lee, Myeong Hwi, Balupuri, Anand, Jung, Ye-rim, Choi, Sungwook, Lee, Areum, Cho, Young Sik, Kang, Nam Sook
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6321621/
https://www.ncbi.nlm.nih.gov/pubmed/30501110
http://dx.doi.org/10.3390/molecules23123136
_version_ 1783385486057799680
author Lee, Myeong Hwi
Balupuri, Anand
Jung, Ye-rim
Choi, Sungwook
Lee, Areum
Cho, Young Sik
Kang, Nam Sook
author_facet Lee, Myeong Hwi
Balupuri, Anand
Jung, Ye-rim
Choi, Sungwook
Lee, Areum
Cho, Young Sik
Kang, Nam Sook
author_sort Lee, Myeong Hwi
collection PubMed
description 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.
format Online
Article
Text
id pubmed-6321621
institution National Center for Biotechnology Information
language English
publishDate 2018
publisher MDPI
record_format MEDLINE/PubMed
spelling pubmed-63216212019-01-14 Design of a Novel and Selective IRAK4 Inhibitor Using Topological Water Network Analysis and Molecular Modeling Approaches Lee, Myeong Hwi Balupuri, Anand Jung, Ye-rim Choi, Sungwook Lee, Areum Cho, Young Sik Kang, Nam Sook Molecules Article 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. MDPI 2018-11-29 /pmc/articles/PMC6321621/ /pubmed/30501110 http://dx.doi.org/10.3390/molecules23123136 Text en © 2018 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Lee, Myeong Hwi
Balupuri, Anand
Jung, Ye-rim
Choi, Sungwook
Lee, Areum
Cho, Young Sik
Kang, Nam Sook
Design of a Novel and Selective IRAK4 Inhibitor Using Topological Water Network Analysis and Molecular Modeling Approaches
title Design of a Novel and Selective IRAK4 Inhibitor Using Topological Water Network Analysis and Molecular Modeling Approaches
title_full Design of a Novel and Selective IRAK4 Inhibitor Using Topological Water Network Analysis and Molecular Modeling Approaches
title_fullStr Design of a Novel and Selective IRAK4 Inhibitor Using Topological Water Network Analysis and Molecular Modeling Approaches
title_full_unstemmed Design of a Novel and Selective IRAK4 Inhibitor Using Topological Water Network Analysis and Molecular Modeling Approaches
title_short Design of a Novel and Selective IRAK4 Inhibitor Using Topological Water Network Analysis and Molecular Modeling Approaches
title_sort design of a novel and selective irak4 inhibitor using topological water network analysis and molecular modeling approaches
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6321621/
https://www.ncbi.nlm.nih.gov/pubmed/30501110
http://dx.doi.org/10.3390/molecules23123136
work_keys_str_mv AT leemyeonghwi designofanovelandselectiveirak4inhibitorusingtopologicalwaternetworkanalysisandmolecularmodelingapproaches
AT balupurianand designofanovelandselectiveirak4inhibitorusingtopologicalwaternetworkanalysisandmolecularmodelingapproaches
AT jungyerim designofanovelandselectiveirak4inhibitorusingtopologicalwaternetworkanalysisandmolecularmodelingapproaches
AT choisungwook designofanovelandselectiveirak4inhibitorusingtopologicalwaternetworkanalysisandmolecularmodelingapproaches
AT leeareum designofanovelandselectiveirak4inhibitorusingtopologicalwaternetworkanalysisandmolecularmodelingapproaches
AT choyoungsik designofanovelandselectiveirak4inhibitorusingtopologicalwaternetworkanalysisandmolecularmodelingapproaches
AT kangnamsook designofanovelandselectiveirak4inhibitorusingtopologicalwaternetworkanalysisandmolecularmodelingapproaches