We modified fluoxetine by incorporating a selenium nucleus enabling a hydroperoxide-inactivating, glutathione peroxidase (GPx)-like activity and paving the way for its use as green catalyst.
Increasing human
life expectancy prompts the development of novel
remedies for cognitive decline: 44 million people worldwide are affected
by dementia, and this number is predicted to triple by 2050. Acetylcholinesterase
and
N
-methyl-
d
-aspartate receptors represent
the targets of currently available drugs for Alzheimer’s disease,
which are characterized by limited efficacy. Thus, the search for
therapeutic agents with alternative or combined mechanisms of action
is wide open. Since variations in 3′,5′-cyclic adenosine
monophosphate, 3′,5′-cyclic guanosine monophosphate,
and/or nitric oxide levels interfere with downstream pathways involved
in memory processes, evidence supporting the potential of phosphodiesterase
(PDE) inhibitors in contrasting neurodegeneration should be
critically considered. For the preparation of this Review, more than
140 scientific papers were retrieved by searching PubMed and Scopus
databases. A systematic approach was adopted when overviewing the
different PDE isoforms, taking into account details on brain localization,
downstream molecular mechanisms, and inhibitors currently under study,
according to available
in vitro
and
in vivo
data. In the context of drug repurposing, a section focusing on
PDE5 was introduced. Original computational studies were performed
to rationalize the emerging evidence that suggests the role of PDE5
inhibitors as multi-target agents against neurodegeneration.
Moreover, since such compounds must cross the blood–brain barrier
and reach inhibitory concentrations in the central nervous system
to exert their therapeutic activity, physicochemical parameters
were analyzed and discussed. Taken together, literature and computational
data suggest that some PDE5 inhibitors, such as tadalafil, represent
promising candidates.
In the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) genome, open
reading frames (ORFs) encode for viral accessory proteins. Among these, Orf7a
structurally resembles the members of the immunoglobulin (Ig) superfamily and
intracellular adhesion molecules (ICAMs), in particular. ICAMs are involved in integrin
binding through lymphocyte function-associated antigen 1 (LFA-1). Based on such
considerations and on previous findings on SARS-CoV, it has been postulated that the
formation of the LFA-1/Orf7a complex could contribute to SARS-CoV-2 infectivity and
pathogenicity. With the current work, we aim at providing insight into this
macromolecular assembly, taking advantage of the recently reported SARS-CoV-2 Orf7a
structure. Protein–protein docking, molecular dynamics (MD) simulations, and a
Molecular Mechanical-Generalized Born Surface Area (MM-GBSA)-based stage were enrolled
to provide refined models.
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