Modulating Interleukins and their Receptors Interactions with Small Chemicals Using In Silico Approach for Asthma

Author(s): Sreyashi Majumdar, Abhirupa Ghosh, Sudipto Saha*

Journal Name: Current Topics in Medicinal Chemistry

Volume 18 , Issue 13 , 2018

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Graphical Abstract:


Asthma is a complex, heterogeneous, airway inflammatory disorder broadly classified into atopic (IgE mediated) and non-atopic asthma. Monoclonal Antibodies (MAbs) and small chemical Protein- Protein Interaction Modulators (PPIMs) are targeted against interleukins (ILs), which play a critical role in asthma. Many MAbs are targeted against ILs and IgE. Anti IgE MAb (Omalizumab) and Anti IL- 5 MAbs (Mepolizumab, Reslizumab) have only been approved by FDA. Most of the MAbs including Tracolizumab, Lebrikizumab, Anrukinzumab (Anti IL-13 MAb), and Brodalumab (Anti IL-17 MAb) are in different phases of clinical trials. Pascolizumab (Anti IL-4 MAb), however, has failed. These MAbs are expensive and may render adverse immune response. Thus, small chemical modulators targeting ILs and their receptors (IL-Rs) are being exploited computationally and further validated experimentally. The complex ILs and IL-Rs available in PDB are best suited for these types of studies. A large number of small chemical modulators against Protein-Protein Interactions (PPIs) have been compiled in a few databases like TIMBAL, 2P2I DB and IPPIDB. Small chemical libraries are used for virtual screening to find novel modulators targeting IL-R binding interface on IL. Molecular dynamic simulations have been further used for disruption mechanism and kinetic studies. IL-2/IL-2R was targeted with clinically tested small molecule modulators like SP4206, and IL-2 levels were known to increase in non-atopic asthma. In the absence of experimentally known modulators against atopic asthma, computational tools are being explored. For example, IL-33 is a target for atopic asthma where IL-33 and its receptor complex structure is available in PDB. In summary, small chemical modulators against ILs are a complementary approach to MAbs and computational tools have been used for identifying these modulators for asthma.

Keywords: Asthma, Interleukins (ILs), Small chemicals, Protein-protein Interaction Modulators (PPIMs), Virtual screening, Molecular dynamic simulation.

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Article Details

Year: 2018
Page: [1123 - 1134]
Pages: 12
DOI: 10.2174/1568026618666180801092839
Price: $65

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