Chemoinformatics Analyses of Tau Ligands Reveal Key Molecular Requirements for the Identification of Potential Drug Candidates against Tauopathies

Tau is a highly soluble protein mainly localized at a cytoplasmic level in the neuronal cells, which plays a crucial role in the regulation of microtubule dynamic stability. Recent studies have demonstrated that several factors, such as hyperphosphorylation or alterations of Tau metabolism, may contribute to the pathological accumulation of protein aggregates, which can result in neuronal death and the onset of a number of neurological disorders called Tauopathies. At present, there are no available therapeutic remedies able to reduce Tau aggregation, nor are there any structural clues or guidelines for the rational identification of compounds preventing the accumulation of protein aggregates. To help identify the structural properties required for anti-Tau aggregation activity, we performed extensive chemoinformatics analyses on a dataset of Tau ligands reported in ChEMBL. The performed analyses allowed us to identify a set of molecular properties that are in common between known active ligands. Moreover, extensive analyses of the fragment composition of reported ligands led to the identification of chemical moieties and fragment combinations prevalent in the more active compounds. Interestingly, many of these fragments were arranged in recurring frameworks, some of which were clearly present in compounds currently under clinical investigation. This work represents the first in-depth chemoinformatics study of the molecular properties, constituting fragments and similarity profiles, of known Tau aggregation inhibitors. The datasets of compounds employed for the analyses, the identified molecular fragments and their combinations are made publicly available as supplementary material.     

Incorporation in Lipid Microparticles of Acid Red 87, a Colorant Used in Tattoo Inks: Effect on Photodegradation Under Simulated Sunlight and Laser Radiation

Tattoo colorants decompose under solar radiation and when exposed to laser light for their removal, leading to the accumulation in the dermis of toxic products. Aim of this study was to develop lipid microparticles (LMs) loaded with the colorant, Acid Red 87 (C.I. 45380) used in tattoo inks, and to investigate the effect of this system on the photostability of the colorant under simulated sunlight or laser irradiation. LMs loaded with C.I. 45380 were prepared by melt emulsification using tristearin and phosphatidylcholine as excipients. They were characterized by optical microscopy, laser diffraction, X-ray diffraction and release studies. Free C.I. 45380 and the colorant-loaded LMs were irradiated with a solar simulator or a Q-switched laser. Irradiation with a solar simulator demonstrated that photodecomposition of C.I. 45380 was markedly reduced by incorporation of the dye in the LMs, from 20.5 ± 4.6% to 1.3 ± 1.8%. Conversely, the laser-induced degradation of the colorant (30.1 ± 6.6%) was not significantly influenced by encapsulation in the LMs (the encapsulated C.I. 45380 loss was 27.4 ± 5.5%). Incorporation of C.I. 45380 in lipid microparticles enhances the photostability under sunlight of tattoo inks containing this colorant, without affecting its laser-induced degradation and hence laser removal efficiency.     

Automorphism groups of Cayley graphs generated by block transpositions and regular Cayley maps

This paper deals with the Cayley graph $\mathrm{Cay}({\mathrm{Sym}}_n,T_n)$, where the generating set consists of all block transpositions. A motivation for the study of these particular Cayley graphs comes from current research in Bioinformatics. As the main result, we prove that $\text{Aut}\left(\mathrm{Cay}({\mathrm{Sym}}_n,T_n)\right)$ is the product of the left translation group and a dihedral group ${\mathsf{D}}_{n+1}$ of order $2(n+1)$. The proof uses several properties of the subgraph $\Gamma$ of $\mathrm{Cay}({\mathrm{Sym}}_n,T_n)$ induced by the set $T_n$. In particular, $\Gamma$ is a $2(n?2)$-regular graph whose automorphism group is ${\mathsf{D}}_{n+1},$ $\Gamma$ has as many as $n+1$ maximal cliques of size $2$, and its subgraph $\Gamma \left(V\right)$ whose vertices are those in these cliques is a 3-regular, Hamiltonian, and vertex-transitive graph. A relation of the unique cyclic subgroup of ${\mathsf{D}}_{n+1}$ of order $n+1$ with regular Cayley maps on ${\text{Sym}}_n$ is also discussed. It is shown that the product of the left translation group and the latter group can be obtained as the automorphism group of a non-$t$-balanced regular Cayley map on ${\text{Sym}}_n$.