Title:Modulating Interleukins and their Receptors Interactions with Small Chemicals Using In Silico Approach for Asthma
Volume: 18
Issue: 13
Author(s): Sreyashi Majumdar, Abhirupa Ghosh and Sudipto Saha*
Affiliation:
- Bioinformatics Centre, Bose Institute, Kolkata,India
Keywords:
Asthma, Interleukins (ILs), Small chemicals, Protein-protein Interaction Modulators (PPIMs), Virtual screening,
Molecular dynamic simulation.
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.
