Eukaryotic translation initiation factor 2-alpha kinase (EIF2AK) proteins inhibit protein synthesis at translation initiation level, in response to various stress conditions, including oxidative stress, heme deficiency, osmotic shock, and heat shock. Origin and functional diversification of EIF2AK sequences remain ambiguous. Here we determine the origin and molecular evolution of EIF2AK proteins in lower eukaryotes and studied the molecular basis of divergence among sub-family sequences. Present work emphasized primitive origin of EIF2AK4 sub-family gene in lower eukaryotes of protozoan lineage. Phylogenetic analysis supported common origin and sub-family based classification of EIF2AKs. Functional divergence studies across sub-families revealed several putative amino acid sites, which assist in altered protein interactions of kinase domains. The data can facilitate designing site-directed experimental studies aiming at elucidating diverse functional aspects of kinase domains regarding down-regulation of protein synthesis.

A series of novel N-1 and C-3 substituted indole derivatives (5a-f) were designed, synthesized and evaluated for their cytotoxic properties, viz Brine Shrimp Lethality Bioassay (BSLB) besides 5-Lipoxygenase (5-LOX) inhibitory activities through in vitro assays. Structure Activity Relation (SAR) studies showed that compound 5d with an LC 50 of 6.49 lM and 5c with an IC 50 of 33.69 lM were found to be interesting for cytotoxicity and 5-LOX inhibitory activity respectively. ª 2015 Production and hosting by Elsevier B.V. on behalf of King Saud University. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

The protein kinase PKR activated by viral dsRNA, phosphorylates the eIF2α, which inhibit the mechanism of translation initiation. Viral evolved proteins mimicking the eIF2α block its phosphorylation and help in the viral replication. To decipher the molecular basis for the PKR’s substrate and inhibitor interaction mechanisms, we carried the molecular dynamics studies on the catalytic domain of PKR in complex with substrate eIF2α, and inhibitors TAT and K3L. The studies conducted show the altered domain movements of N lobe, which confers open and close state to the substrate-binding cavity. In addition, PKR exhibits variations in the secondary structural transition of the activation loop residues, and inter molecular contacts with the substrate and the inhibitors. Phosphorylation of the P+1 loop at the Thr-451 increases the affinity of the binding proteins exhibiting its role in the phosphorylation events. The implications of structural mechanisms uncovered will help to understand the basis of the evolution of the host-viral and the viral replication mechanisms.

The title compound bis[2-hydroxybenzylidenehydrazono)(methylthio)methyl]disulfide (1), an S-methyldithiocarbazate derivative with a disulfide bond has been synthesized by the condensation of 2-hydroxybenzaldehyde with S-methyldithiocarbazate. It has been characterized by elemental analyses, 1 H, 13 C NMR and FT-IR spectroscopy and mass spectrometry. The single crystal X-ray structure shows that the compound exists in a tautomeric thione form with the dithiocarbazate fragment adopting an EE configuration with respect to the C=N bond of the benzylidene moiety. The thermal behaviour of the compound has been studied using thermogravimetric analysis (TGA). The molecular geometry of the compound in the ground state has been optimized using density functional theory (DFT/B3LYP) method with the 6-311++G(d,p) basis sets. Molecular docking of the compound with human carbonic anhydrase II has been performed to probe the nature of interaction.