Have you a compound in your lab, which was not successful against the designed target, or a drug that is no more attractive? The drug repurposing represents the right way to reconsider them. It can ...be defined as the modern and rationale approach of the traditional methods adopted in drug discovery, based on the knowledge, insight and luck, alias known as serendipity. This repurposing approach can be applied both in silico and in wet. In this review we report the molecular modeling facilities that can be of huge support in the repurposing of drugs and/or unsuccessful lead compounds. In the last decades, different methods were proposed to help the scientists in drug design and in drug repurposing. The steps strongly depend on the approach applied. It could be a ligand or a structure based method, correlated to the use of specific means. These processes, starting from a compound with potential therapeutic properties and a sizeable number of toxicity passed tests, can successfully speed up the very slow development of a molecule from bench to market. Herein, we discuss the facilities available to date, classifying them by methods and types. We have reported a series of databases, ligand and structure stand-alone software, and of web-based tools, which are free accessible to scientific community. This review does not claim to be exhaustive, but can be of interest to help in drug repurposing through in silico methods, as a valuable tool for the medicinal chemistry community.
Alzheimer's Disease (AD) is a neurodegenerative disorder with a complex aetiology displayed by multiple pathogenic factors. The APOE ɛ4 allele represents the only established genetic risk factor for ...sporadic AD; in addition, previous findings on three single nucleotide polymorphisms (SNPs) located on the APOE promoter region, have led to a growing interest in their potential role in AD pathogenesis. The −491 A/T promoter polymorphism has been the one most frequently shown to be associated with AD, as it influences the APOE coding region transcription. The aim of this study was to evaluate the possible effect of the −491 A/T polymorphism on the cognitive profile of sporadic AD patients with a disease severity ranging from mild to moderate. Our results showed that patients carrying the −491 AA genotype had poorer cognitive performances than the −491 AT ones, statistically significant in demanding tests of visual attention, especially for the late-onset AD (LOAD). No further differences on cognitive profile were observed when stratifying AA and AT patients according to their APOE genotype. These results suggest a possible functional effect of the −491 A/T promoter on the neuropsychological performances of AD. This role seems to be independent of APOE genotype. In fact the effect of −491 A/T occurs predominantly on attention while the APOE ɛ4 allele mainly affects memory performances. According to the biological effect exerted on APOE transcription, the −491 A/T polymorphism could be considered a disease modifier more than a risk factor for sporadic AD.
Naive epiblast and embryonic stem cells (ESCs) give rise to all cells of adults. Such developmental plasticity is associated with genome hypomethylation. Here, we show that LIF-Stat3 signaling ...induces genomic hypomethylation via metabolic reconfiguration. Stat3
ESCs show decreased α-ketoglutarate production from glutamine, leading to increased Dnmt3a and Dnmt3b expression and DNA methylation. Notably, genome methylation is dynamically controlled through modulation of α-ketoglutarate availability or Stat3 activation in mitochondria. Alpha-ketoglutarate links metabolism to the epigenome by reducing the expression of Otx2 and its targets Dnmt3a and Dnmt3b. Genetic inactivation of Otx2 or Dnmt3a and Dnmt3b results in genomic hypomethylation even in the absence of active LIF-Stat3. Stat3
ESCs show increased methylation at imprinting control regions and altered expression of cognate transcripts. Single-cell analyses of Stat3
embryos confirmed the dysregulated expression of Otx2, Dnmt3a and Dnmt3b as well as imprinted genes. Several cancers display Stat3 overactivation and abnormal DNA methylation; therefore, the molecular module that we describe might be exploited under pathological conditions.
FTIR spectroscopy is applied to monitor the effects caused by fluorinated precursors (1–10
mol%) in the sol–gel synthesis of silica glasses, either pure or doped with Ce and Er. In pure samples the ...Si–OH level is heavily reduced to ∼3
×
10
−3
mol%. In doped samples the effect is more limited. The presence of residual fluorine, proved by the Si–F vibrational absorption at ∼950
cm
−1, causes deep changes in the rare-earth (RE) crystal field spectra, which are characterized by narrow absorption lines. The lines broaden if the temperature is increased from 9 to 300
K. The result is discussed in terms either of local ordering around the rare earth ion or by its partial decoupling from the disordered host matrix, due to the creation of network terminating sites.
Photoluminescence in fluorine-modified Sn-doped silica has been analyzed by means of synchrotron radiation in the UV and vacuum-UV, from 120 to 330
nm, looking at the optical activity of ...oxygen-deficient-centers ODC(II) in Sn-substituted cationic sites. The comparison between F-modified Sn-doped samples and previous data on F-free Sn-doped material evidences differences in the intensity of the 3.2
eV emission band excited at 3.7
eV, and in the thermal dependence of the intensity of this emission excited via intersystem crossing. The role of fluorine in modifying the optical activity of ODC(II) and in the SnO
2 clustering is discussed, showing that an efficient excitation transfer may be activated from SnO
2 to the Sn-variant of ODC(II).
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