Abstract
IntroductionGulf War Illness (GWI) currently has no known cure and affects soldiers deployed during the Persian Gulf War. It is thought to originate from exposure to neurotoxicants combined with battlefield stress, and previous research indicates that treatment first involves inhibition of interleukin-2 and tumor necrosis factor alpha, followed by the glucocorticoid receptor. However, the off-target effects of pharmaceuticals hinder development of a drug treatment therapy.Materials and MethodsAutoDock 4.2, AutoDock Vina, and Schrodinger’s Glide were used to perform consensus docking, a computational technique where pharmaceuticals are screened against targets using multiple scoring algorithms to obtain consistent binding affinities. FDA approved pharmaceuticals were docked against the above-mentioned immune and stress targets to determine a drug therapy for GWI. Additionally, the androgen and estrogen targets were screened to avoid pharmaceuticals with off-target interactions.ResultsWhile suramin bound to both immune targets with high affinity, top binders of the hormonal and glucocorticoid targets were non-specific towards their respective proteins, possibly due to high structure similarity between these proteins.ConclusionsDevelopment of a drug treatment therapy for GWI is threatened by the tight interplay between the immune and hormonal systems, often leading to drug interactions. Increasing knowledge of these interactions can lead to break-through therapies.
Highlights
Gulf War Illness (GWI) currently has no known cure and affects soldiers deployed during the Persian Gulf War
A major hypothesis of GWI pathophysiology proposes that toxicant exposure, aggravated by stress, triggers a neuroinflammatory cascade leading to altered homeostatic regulation.[1–3]
AutoDock 4.2 and Vina 1.1.2 (VINA) were excluded from AR 2pnu, ER 4ivy, and ER 4iwf because their predicted poses for the known binders were above the 2.0 Å root mean squared deviation (RMSD) cutoff range
Summary
Gulf War Illness (GWI) currently has no known cure and affects soldiers deployed during the Persian Gulf War. Craddock et al.[7] utilized discrete logic models to determine a treatment course that would correct the altered homeostatic regulation in individuals with GWI This multi-intervention treatment course comprised of inhibiting Th1 immune cytokines interleukin-2 (IL-2) and tumor necrosis factor alpha (TNFα), directly followed by inhibition of the glucocorticoid receptor (GCR), involved with the stress response; a specific pharmaceutical combination for this treatment course has yet to be determined. Due to the tight regulation between the hormonal and immune systems,[11] the androgen (AR) and estrogen (ER) targets were screened to ensure that only drugs specific to IL-2, TNF- α, and GCR were chosen, reducing the chances of offtarget interactions. FDA-approved drugs were used because their toxicity and efficacy have already been extensively profiled, they are readily available for in vitro
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