Exploring N1-p-Fluorobenzyl-Cymserine as an Inhibitor of 5-Lipoxygenase as a Candidate for Type 2 Diabetes and Neurodegenerative Disorder Treatment
Qurrat ul Ain, Nigel H. Greig, Muhammad S. Nawaz, Sajid Rashid and Mohammad A. Kamal
Affiliation: (N.H. Greig) Drug Design & Development Section, Intramural Research Program, National Institute on Aging, National Institutes of Health, Baltimore, MD 21224, USA.
Keywords: -lipoxygenase, docking, fluorobenzylcymserine, 5type 2 diabetes.
Developing a single selective ligand to a target relevant to two mechanistically interlinked diseases, such as
type 2 diabetes mellitus (T2DM) and a neurodegenerative disorder, like Parkinson’s disease or Alzheimer’s disease,
provides the potential for an effective treatment that may impact both. The enzyme 5-lipoxygenase (5-LOX) has been
revealed responsible for producing fatty acid molecules, leukotrienes. These leukotrienes are known to produce
inflammatory responses in asthma and allergic reactions, to induce a reduction of tyrosine hydroxylase in brain, and are
involved in the development of cardiac strokes, obesity and type 2 diabetes. N1-p-fluorobenzyl-cymserine (FBC), an
analogue of cymserine and a known cholineterase inhibitor, was evaluated for inhibition of pleiotropic 5-LOX in our
study. The stable 3D structure of 5-LOX was obtained from the Protein Data Bank (PDB) database and was implied for
homology modeling of four reported mutant models. Each generated model was submitted to the Protein Model Database
(PMDB) and employed for measuring inhibition and ligand efficiency of FBC with support of molecular docking. For
each model, normal as well as mutant, FBC yielded remarkable inhibition constant values, with exothermic free binding
energies. The current study revealed a highly reactive narrow fissure near the non-heme iron binding pocket of 5-LOX
that contains residues crucial for 5-LOX stability and FBC binding. Investigating the binding of FBC with stabilized and
destabilized 5-LOX structures confirmed it as a candidate therapeutic inhibitor worthy of assessment in preclinical models
of T2DM and neurodegeneration.
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