Molecular Similarity Perception Based on Machine-Learning Models.

Molecular similarity is an impressively broad topic with many implications in several areas of chemistry. Its roots lie in the paradigm that 'similar molecules have similar properties'. For this reason, methods for determining molecular similarity find wide application in pharmaceutical companies, e.g., in the context of structure-activity relationships. The similarity evaluation is also used in the field of chemical legislation, specifically in the procedure to judge if a new molecule can obtain the status of orphan drug with the consequent financial benefits. For this procedure, the European Medicines Agency uses experts' judgments. It is clear that the perception of the similarity depends on the observer, so the development of models to reproduce the human perception is useful. In this paper, we built models using both 2D fingerprints and 3D descriptors, i.e., molecular shape and pharmacophore descriptors. The proposed models were also evaluated by constructing a dataset of pairs of molecules which was submitted to a group of experts for the similarity judgment. The proposed machine-learning models can be useful to reduce or assist human efforts in future evaluations. For this reason, the new molecules dataset and an online tool for molecular similarity estimation have been made freely available.

Modelling of short synthetic antifreeze peptides: Insights into ice-pinning mechanism.

Organisms living in icy environments produce antifreeze proteins to control ice growth and recrystallization. It has been proposed that these molecules pin the surface of ice crystals, thus inducing the formation of a curved surface that arrests crystal growth. Such proteins are very appealing for many potential applications in food industry, material science and cryoconservation of organs and tissues. Unfortunately, their structural complexity has seriously hampered their practical use, while efficient and accessible synthetic analogues are highly desirable. In this paper, we used molecular dynamics based techniques to model the interaction of three short antifreeze synthetic peptides with an ice surface. The employed protocols succeeded in reproducing the ice pinning action of antifreeze peptides and the consequent ice growth arrest, as well as in distinguishing between antifreeze and control peptides, for which no such effect was observed. Principal components analysis of peptides trajectories in different simulation settings permitted to highlight the main structural features associated to antifreeze activity. Modeling results are highly correlated with experimentally measured properties, and insights on ice-peptide interactions and on conformational patterns favoring antifreeze activity will prompt the design of new and improved antifreeze peptides.

The Origin of the σ-Hole in Halogen Atoms: a Valence Bond Perspective.

A detailed Valence Bond-Spin Coupled analysis of a series of halogenated molecules is here reported, allowing to get a rigorous ab initio demonstration of the qualitative models previously proposed to explain the origin of halogen bonding. The concepts of σ-hole and negative belt observed around the halogen atoms in the electrostatic potential maps are here interpreted by analysis of the relevant Spin Coupled orbitals.

Adaptative value of a PKC-PKI55 feedback loop of inhibition that prevents the kinase's deregulation.

A 168-bp amplification product was obtained in RT-PCR experiments using a degenerate oligonucleotide designed on a five-amino acid sequence of IN, a 7-kDa protein, previously characterized as a PKC inhibitor. It was included in the coding ORF of the 1530-bp-long IMAGE clone ID 38900 (accession numbers R51337 and R51448) that produces a translation product of 6.5 kDa. The translation of the ORF conceptual reading frame allowed the preparation of the synthetic protein PKI55, which was found to inhibit and degrade both untreated nPKC d isozymes and activated cPKC isozymes. The PKI55 gene is localized in chromosome 2q35. The Repeat Maskers output showed a 533-bp-long LTR32/ERVL segment that included the PKI55 coding sequence and a complete regulatory region. The coding sequence and the structure of PKI55 were detected in a brain cDNA of Macaca fascicularis (diverged from human lineages about 25 Myr ago). Three other human genes with over 60% identities with PKI55 were identified in three different loci (i.e., chromosomes 10, 15, and 20.) Synthesis of PKI55 was stimulated by PKC activation. A feedback loop of inhibition is established. When the PKCs are overactivated, PKI55 induces degradation of the enzyme and prevents the isozyme overexpression implicated in a number of important diseases including cancer, diabetes, and disorders of the immune system. The presence of the PKI55 sequence in Macaca fascicularis as well as in human chromosomes 10, 15, and 20 indicates a selective advantage for the PKI55 sequence and the adaptive value of the feedback mechanism.

Protein kinase C activity, translocation, and selective isoform subcellular redistribution in the rat cerebral cortex after in vitro ischemia.

Protein kinase C (PKC) involvement in ischemia-induced neuronal damage has been investigated in superfused rat cerebral cortex slices submitted to 15 min of oxygen-glucose deprivation (OGD) and in primary cultures of rat cortical neurons exposed to 100 microM glutamate (GLU) for 10 min. OGD significantly increased the total PKC activity in the slices, mostly translocated in the particulate fraction. After 1 hr of reperfusion, the total PKC activity was reduced and the translocated fraction dropped by 84% with respect to the control. Western blot analysis of OGD samples showed an increase in total beta(2) and epsilon PKC isoform levels. After reperfusion, the total levels of alpha, beta(1), beta(2) and gamma isoforms were significantly reduced, whereas the epsilon isoform remained at an increased level. Endogenous GLU release from OGD slices increased to about 15 times the basal values after 15 min of oxygen-glucose deprivation, and to 25 and 35 times the basal level in the presence of the PKC inhibitors staurosporine (0.1 microM) and bisindolylmaleimide (1 microM), respectively. Western blot analysis of GLU-treated cortical neurons showed a significant decrease only in the total level of beta(2) isoforms. Cell survival was reduced to 31% in GLU-treated neuronal cultures; PKC inhibitors were not able to modify this effect. These findings demonstrate that the cell response to OGD and GLU involves PKC in a complex way. The net role played by PKC during OGD may be to reduce GLU release and, consequently, neurotoxicity. The isoforms beta(2) and epsilon are affected the most and may play a significant role in the mechanisms underlying neurotoxicity/neuroprotection.