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Quinoline-3-carboxamides are an essential class of drug-like small molecules that are known to inhibit the phosphatidylinositol 3-kinase-related kinases (PIKK) family kinases. The quinoline nitrogen is shown to bind to the hinge region of the kinases, making them competitive inhibitors of adenosine triphosphate (ATP). We have previously designed and synthesized quinoline-3-carboxamides as potential ataxia telangiectasia mutated (ATM) kinase inhibitors to function as an adjuvant treatment with DNA damaging agents. This article discusses the molecular docking studies performed with these derivatives with the DNA damage and response (DDR) kinases-ATM, ataxia telangiectasia and rad3 related (ATR), and DNA dependent protein kinase catalytic subunit (DNA-PKcs) and highlights their selectivity towards ATM kinase. Docking studies were also performed with mTOR and PI3Kγ, which are close homologs of the DDR kinases. Molecular dynamics simulations were performed for one of the inhibitors against all the enzymes to establish the stability of the interactions involved. Finally, the absorption, distribution, metabolism, and excretion (ADME) properties of the inhibitors were predicted using the QikProp manual in Maestro. In conclusion, the molecules synthesized showed high selectivity towards the ATM kinase in comparison with the other kinases, though the sequence similarity between them was relatively high.

Phosphatidylinositol-3 kinase-related kinases (PIKKs) is a class of six unique serine/threonine kinases that are characterized as high molecular mass colossal proteins present in multicellular organisms. They predominantly regulate the innumerable eukaryotic cellular processes, for instance, cell-signaling cascades related to DNA damage and repair, cell growth and proliferation, cell cycle arrest, genome surveillance, gene expression and many other important yet diverse functions. A characteristic PIKK member comprises of an N-terminal HEAT domain, followed by FAT domain, a highly conserved kinase catalytic domain, and a C-terminal FATC domain. In this comprehensive review, we reassess and discuss various established functions of all the six PIKK members with each function corroborated by their structural topology. In addition to the domain architecture of these atypical kinases, their specific inhibitors have been briefly deliberated. This review gives us the impression of the emergent importance of PIKKs, which, despite of their complexity, are the hub of research with respect to the inhibitor development.

Asteroid and cometary impacts have been considered one of the possible routes for exogenous delivery of organics to the early Earth. It is well established that amino acids can be synthesized due to impact-driven shock processesing of simple molecules and that amino acids can survive the extreme conditions of impact events. In the present study, we simulate impact-induced shock conditions utilizing a shock tube that can maintain a reflected shock temperature of about 5,500 K for 2 ms time scale. We have performed shock processing of various combinations of amino acids with subsequent morphological analysis carried out using Scanning Electron Microscope (SEM), revealing that the shock processed amino acids demonstrate an extensive range of complex structures. These results provide evidence for the further evolution of amino acids in impact-induced shock environments leading to the formation of complex structures and thus providing a pathway for the origin of life.

Impact delivery of prebiotic compounds to the early Earth from an impacting comet is considered to be one of the possible ways by which prebiotic molecules arrived on the Earth. Given the ubiquity of impact features observed on all planetary bodies, bolide impacts may be a common source of organics on other planetary bodies both in our own and other solar systems. Biomolecules such as amino acids have been detected on comets and are known to be synthesized due to impact-induced shock processing. Here we report the results of a set of hypervelocity impact experiments where we shocked icy mixtures of amino acids mimicking the icy surface of planetary bodies with high-speed projectiles using a two-stage light gas gun and analyzed the ejecta material after impact. Electron microscopic observations of the ejecta have shown the presence of macroscale structures with long polypeptide chains revealed from LCMS analysis. These results suggest a pathway in which impact on cometary ices containing building blocks of life can lead to the synthesis of material architectures that could have played a role in the emergence of life on the Earth and which may be applied to other planetary bodies as well.

The title compound, C12H11NO3, is an intermediate used in the synthesis of many drug-like molecules. The molecule is almost planar, with the phenyl ring inclined to the isoxazole ring by 0.5 (1)°. The ester moiety has an extended conformation and is almost in the same plane with respect to the isoxazole ring, as indicated by the O—C—C—N torsion angle of −172.86 (18)°. In the crystal, molecules are linked via pairs of C—H...O hydrogen bonds with the same acceptor atom, forming inversion dimers with two R21(7) ring motifs. The molecules stack in layers lying parallel to (10-3). Analysis using Hirshfeld surface generation and two-dimensional fingerprint plots explores the distribution of weak intermolecular interactions in the crystal structure.

In this report, we describe the structural characterization of three 2,4-disubstituted-dihydropyrimidine-5-carbonitrile derivatives, namely 2-{[(4-nitrophenyl)methyl]sulfanyl}-6-oxo-4-propyl-1,6-dihydropyrimidine-5-carbonitrile 1, 4-(2-methylpropyl)-2-{[(4-nitrophenyl)methyl]sulfanyl}-6-oxo-1,6-dihydropyrimidine-5-carbonitrile 2, and 2-[(2-ethoxyethyl)sulfanyl]-6-oxo-4-phenyl-1,6-dihydropyrimidine-5-carbonitrile monohydrate 3. An X-ray diffraction analysis revealed that these compounds were crystallized in the centrosymmetric space groups and adopt an L-shaped conformation. One of the compounds (3) crystallized with a water molecule. A cyclic motif (R22(8)) mediated by N–H···O hydrogen bond was formed in compounds 1 and 2, whereas the corresponding motif was not favorable, due to the water molecule, in compound 3. The crystal packing of these compounds was analyzed based on energy frameworks performed at the B3LYP/6-31G(d,p) level of theory. Various inter-contacts were characterized using the Hirshfeld surface and its associated 2D-fingerprint plots. Furthermore, a molecular docking simulation was carried out to assess the inhibitory potential of the title compounds against the human dihydrofolate reductase (DHFR) enzyme.

The building blocks of life, amino acids, are believed to have been synthesized in the extreme conditions that prevail in space, starting from simple molecules containing hydrogen, carbon, oxygen and nitrogen. However, the fate and role of amino acids when they are subjected to similar processes largely remain unexplored. Here we report, for the first time, that shock processed amino acids tend to form complex agglomerate structures. Such structures are formed on timescales of about 2 ms due to impact induced shock heating and subsequent cooling. This discovery suggests that the building blocks of life could have self-assembled not just on Earth but on other planetary bodies as a result of impact events. Our study also provides further experimental evidence for the ‘threads’ observed in meteorites being due to assemblages of (bio)molecules arising from impact-induced shocks.