Scaffold mining of kinase hinge binders in crystal structure database

Protein kinases are the second most prominent group of drug targets, after G-protein-coupled receptors. Despite their distinct inhibition mechanisms, the majority of kinase inhibitors engage the conserved hydrogen bond interactions with the backbone of hinge residues. We mined Pfizer internal crystal structure database (CSDb) comprising of several thousand of public as well as internal X-ray binary complexes to compile an inclusive list of hinge binding scaffolds. The minimum ring scaffolds with directly attached hetero-atoms and functional groups were extracted from the full compounds by applying a rule-based filtering procedure employing a comprehensive annotation of ATP-binding site of the human kinase complements. The results indicated large number of kinase inhibitors of diverse chemical structures are derived from a relatively small number of common scaffolds, which serve as the critical recognition elements for protein kinase interaction. Out of the nearly 4,000 kinase-inhibitor complexes in the CSDb we identified approximately 600 unique scaffolds. Hinge scaffolds are overwhelmingly flat with very little sp3 characteristics, and are less lipophilic than their corresponding parent compounds. Examples of the most common as well as the uncommon hinge scaffolds are presented. Although the most common scaffolds are found in complex with multiple kinase targets, a large number of them are uniquely bound to a specific kinase, suggesting certain scaffolds could be more promiscuous than the others. The compiled collection of hinge scaffolds along with their three-dimensional binding coordinates could serve as basis set for hinge hopping, a practice frequently employed to generate novel invention as well as to optimize existing leads in medicinal chemistry.     

Unambiguous identification of three beta-decaying isomers in 70Cu

Using resonant laser ionization, beta-decay studies, and for the first time mass measurements, three beta-decaying states have been unambiguously identified in 70Cu. A mass excess of -62 976.1(1.6) keV and a half-life of 44.5(2) s for the (6-) ground state have been determined. The level energies of the (3-) isomer at 101.1(3) keV with T(1/2)=33(2) s and the 1+ isomer at 242.4(3) keV with T(1/2)=6.6(2) s are confirmed by high-precision mass measurements. The low-lying levels of 70Cu populated in the decay of 70Ni and in transfer reactions compare well with large-scale shell-model calculations, and the wave functions appear to be dominated by one proton-one neutron configurations outside the closed Z=28 shell and N=40 subshell. This does not apply to the 1+ state at 1980 keV which exhibits a particular feeding and deexcitation pattern not reproduced by the shell-model calculations.     

The mass of 22Mg

Mass measurements with a relative precision of better than 1.5 x 10(-8) were performed on 22Mg and its reaction partners 21Na and 22Na with the ISOLTRAP Penning trap mass spectrometer at CERN, yielding the mass excesses D(22Mg)=-399.92(27) keV, D(21Na)=-2184.71(21) keV, and D(22Na)=-5181.56(16) keV. The importance of these results is twofold. First, a comparative half-life (Ft value) has been obtained for the superallowed beta decay of 22Mg to further test the conserved-vector-current hypothesis. Second, the resonance energy for the 21Na proton capture reaction has been independently determined, allowing direct comparisons of observable gamma radiation in nova explosions with the yield expected from models.     

Mass Measurements on Short-Lived Nuclides with ISOLTRAP

Penning trap mass spectrometry has reached a state that allows its application to very short-lived nuclides available from various sources of radioactive beams. Mass values with outstanding accuracy are achieved even far from stability. This paper illustrates the state of the art by summarizing the status of the ISOLTRAP experiment at ISOLDE/CERN. Furthermore, results of mass measurements on unstable rare earth isotopes will be given. This revised version was published online in July 2006 with corrections to the Cover Date.     

In-trap decay spectroscopy for 2�ͦ¦� decay experiments

Knowledge of 2??|? nuclear matrix elements is essential to probe the theoretical framework of 0??|? decays. At TITAN, TRIUMF??s Ion Trap for Atomic and Nuclear science, a novel technique has been developed to measure electron capture branches of virtual intermediate nuclei in ?|? decays. During two experiments with radioactive ^{124, 126}Cs isotopes the feasibility of this new method was proven.     

Precision mass measurements of neutron halo nuclei using the TITAN Penning trap

Precise atomic mass determinations play a key role in various fields of physics, including nuclear physics, testing of fundamental symmetries and constants and atomic physics. Recently, the TITAN Penning trap measured the masses of several neutron halos. These exotic systems have an extended, diluted, matter distribution that can be modelled by considering a nuclear core surrounded by a halo formed by one or more of loosely bound neutrons. Combined with laser spectroscopy measurements of isotopic shifts precise masses can be used to obtain reliable charge radii and two-neutron-seperation energies for these halo nuclei. It is shown that these results can be used as stringent tests of nuclear models and potentials providing an important metric for our understanding of the interactions in all nuclei.