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Targeting the TGF‐β Receptor with Kinase Inhibitors for Scleroderma Therapy
Author(s) -
Cong Lin,
Xia ZhiKuan,
Yang RongYa
Publication year - 2014
Publication title -
archiv der pharmazie
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.468
H-Index - 61
eISSN - 1521-4184
pISSN - 0365-6233
DOI - 10.1002/ardp.201400116
Subject(s) - kinase , transforming growth factor , molecular mechanics , scleroderma (fungus) , chemistry , molecular dynamics , pharmacology , microbiology and biotechnology , cancer research , computational biology , biology , biochemistry , immunology , computational chemistry , inoculation
Scleroderma (systemic sclerosis) is a connective tissue disease that affects various organ systems; the treatment of scleroderma is still difficult and remains a challenge to the clinician. Recently, kinase inhibitors have shown great potential against fibrotic diseases and, specifically, the transforming growth factor‐β receptor (TGF‐βR) was found as a new and promising target for scleroderma therapy. In the current study, we propose that the large pool of existing kinase inhibitors could be exploited for inhibiting the TGF‐βR to suppress scleroderma. In this respect, we developed a modeling protocol to systematically profile the inhibitory activities of 169 commercially available kinase inhibitors against the TGF‐βR, from which five promising candidates were selected and tested using a standard kinase assay protocol. Consequently, two molecular entities, namely the PKB inhibitor MK‐2206 and the mTOR C1/C2 inhibitor AZD8055, showed high potency when bound to the TGF‐βR, with IC 50 values of 97 and 86 nM, respectively, which are close to those of the recently developed TGF‐βR selective inhibitors SB525334 and LY2157299 (IC 50 = 14.3 and 56 nM, respectively). We also performed atomistic molecular dynamics simulations and post‐molecular mechanics/Poisson–Boltzmann surface area analyses to dissect the structural basis and energetic properties of intermolecular interactions between the TGF‐βR kinase domain and these potent compounds, highlighting intensive nonbonded networks across the tightly packed interface of non‐cognate TGF‐βR‐inhibitor complexes.