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.

Increasing 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 (AChE) and N-methyl-D-aspartate (NMDA) receptors represent the targets of currently available drugs for Alzheimer’s disease (AD), that are anyway characterized by limited efficacy. Thus, the search for therapeutic agents with alternative or combined mechanisms of action is wide open. Since variations in cAMP, cGMP and/or NO levels interfere with downstream pathways involved in memory processes, evidences 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 evidences that suggest the role of PDE5 inhibitors as multi-target agents against neurodegeneration. Moreover, since such compounds must cross the blood brain barrier (BBB) and reach inhibitory concentrations in CNS 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 1998, sildenafil was marketed as the first FDA-approved oral drug for the treatment of erectile dysfunction (ED). During the last two decades, the commercialization of other synthetic phosphodiesterase 5 (PDE5) inhibitors has been paralleled by the rise of remedies based on natural molecules from different chemical classes (flavonoids, polyphenols and alkaloids in general). In this work, a set of in silico tools were applied to study a panel of 30 natural compounds claimed to be effective against ED in the scientific literature or in folk medicine. First, pharmacokinetic properties were analysed to exclude the compounds lacking in specific drug-like features. Estimated binding energy for PDE5 and selectivity towards other PDE isoforms were then considered to highlight some promising molecules. Finally, a detailed structural investigation of the interaction pattern with PDE in comparison with sildenafil was conducted for the best performing compound of the set.

Fluoxetine finds application in the treatment of depression and mood disorders. This selective serotonin-reuptake inhibitor (SSRI) also contrasts oxidative stress by direct ROS scavenging, modulation of the endogenous antioxidant defense system, and/or enhancement of the serotonin antioxidant capacity. We synthesised some fluoxetine analogues incorporating a selenium nucleus, thus expanding its antioxidant potential by enabling a hydroperoxides-inactivating, glutathione peroxidase (GPx)-like activity. Radical scavenging and peroxidatic activity were combined in a water-soluble, drug-like, tandem antioxidant molecule. Selenofluoxetine derivatives were reacted with H₂O₂ in water, and the mechanistic details of the reaction were unravelled combining nuclear magnetic resonance (NMR), electrospray ionisation-mass spectrometry (ESI-MS) and quantum chemistry calculations. The observed oxidation–elimination process led to the formation of seleninic acid and cinnamylamine in a trans-selective manner. This mechanism is likely to be extended to other substrates for the preparation of unsaturated cinnamylamines.