The benefits of in silico modeling to identify possible small-molecule drugs and their off-target interactions

Accepted for publication in a future issue of Future Medicinal Chemistry.The research into the use of small molecules as drugs continues to be a key driver in the development of molecular databases, computer-aided drug design software and collaborative platforms. The evolution of computational approaches is driven by the essential criteria that a drug molecule has to fulfill, from the affinity to targets to minimal side effects while having adequate absorption, distribution, metabolism, and excretion (ADME) properties. A combination of ligand- and structure-based drug development approaches is already used to obtain consensus predictions of small molecule activities and their off-target interactions. Further integration of these methods into easy-to-use workflows informed by systems biology could realize the full potential of available data in the drug discovery and reduce the attrition of drug candidates.Peer reviewe

Kemiallisen ympäristön tutkiminen XPS-menetelmällä

Tiivistelmä. Fotoelektronispektroskopiassa hyödynnetään Albert Einsteinin selittämää valosähköistä ilmiötä, jolla määritetään liike-energia näytteestä irrotetuille fotoelektroneille. Näillä tiedoilla aseistettuna selvitämme näytemateriaalin elektronivyörakennetta, josta voimme päätellä näytteen koostumuksen. Tässä tutkielmassa käsittelen tarkemmin röntgenfotoelektronispektroskopiaa ja sen soveltamista atomien kemiallisen ympäristön analysoimiseen. Röntgenfotoelektronispektroskopia, eli XPS ("X-ray photoelectron spectroscopy") on yksi materiaalitutkimuksen menetelmistä. Painottaen menetelmän hyötyä aineanalyysissä, sitä kutsutaan myös elektronispektroskopiaksi kemialliseen analyysiin, mikä lyhennetään ESCA ("Electron spectroscopy for chemical analysis"). Erikoisuutena muihin spektroskooppisiin menetelmiin XPS kertoo, alkuainepitoisuuksien lisäksi, myös näytteen kemiallisista sidoksista

Iterative approach to computational enzyme design

A general approach for the computational design of enzymes to catalyze arbitrary reactions is a goal at the forefront of the field of protein design. Recently, computationally designed enzymes have been produced for three chemical reactions through the synthesis and screening of a large number of variants. Here, we present an iterative approach that has led to the development of the most catalytically efficient computationally designed enzyme for the Kemp elimination to date. Previously established computational techniques were used to generate an initial design, HG-1, which was catalytically inactive. Analysis of HG-1 with molecular dynamics simulations (MD) and X-ray crystallography indicated that the inactivity might be due to bound waters and high flexibility of residues within the active site. This analysis guided changes to our design procedure, moved the design deeper into the interior of the protein, and resulted in an active Kemp eliminase, HG-2. The cocrystal structure of this enzyme with a transition state analog (TSA) revealed that the TSA was bound in the active site, interacted with the intended catalytic base in a catalytically relevant manner, but was flipped relative to the design model. MD analysis of HG-2 led to an additional point mutation, HG-3, that produced a further threefold improvement in activity. This iterative approach to computational enzyme design, including detailed MD and structural analysis of both active and inactive designs, promises a more complete understanding of the underlying principles of enzymatic catalysis and furthers progress toward reliably producing active enzymes

Magnetospheric response to the solar wind as indicated by the cross-polar potential drop and the low-latitude asymmetric disturbance field

International audienceThe cross-polar potential drop ?pc and the low-latitude asymmetric geomagnetic disturbance field, as indicated by the mid-latitude ASY-H magnetic index, are used to study the average magnetospheric response to the solar wind forcing for southward interplanetary magnetic field conditions. The state of the solar wind is monitored by the ACE spacecraft and the ionospheric convection is measured by the double probe electric field instrument on the Astrid-2 satellite. The solar wind-magnetosphere coupling is examined for 77 cases in February and from mid-May to mid-June 1999 by using the interplanetary magnetic field Bz component and the reconnection electric field. Our results show that the maximum correlation between ?pc and the reconnection electric field is obtained approximately 25 min after the solar wind has reached a distance of 11 RE from the Earth, which is the assumed average position of the magnetopause. The corresponding correlation for ASY-H shows two separate responses to the reconnection electric field, delayed by about 35 and 65 min, respectively. We suggest that the combination of the occurrence of a large magnetic storm on 18 February 1999 and the enhanced level of geomagnetic activity which peaks at Kp = 7- may explain the fast direct response of ASY-H to the solar wind at 35 min, as well as the lack of any clear secondary responses of ?pc to the driving solar wind at time delays longer than 25 min

Uniaxial strain detwinning of CaFe2As2 and BaFe2As2: optical and transport study

TThe parent compounds of iron-arsenide superconductors, $A$Fe$_{2}$As$_{2}$ ($A$=Ca, Sr, Ba), undergo a tetragonal to orthorhombic structural transition at a temperature $T_{\mathrm{TO}}$ in the range 135 to 205K depending on the alkaline earth element. Below $T_{\mathrm{TO}}$ the free standing crystals split into equally populated structural domains, which mask intrinsic, in-plane, anisotropic properties of the materials. Here we demonstrate a way of mechanically detwinning CaFe$_{2}$As$_{2}$ and BaFe$_{2}$As$_{2}$. The detwinning is nearly complete, as demonstrated by polarized light imaging and synchrotron $X$-ray measurements, and reversible, with twin pattern restored after strain release. Electrical resistivity measurements in the twinned and detwinned states show that resistivity, $\rho$, decreases along the orthorhombic $a_{o}$-axis but increases along the orthorhombic $b_{o}$-axis in both compounds. Immediately below $T_{\mathrm{TO}}$ the ratio $\rho_{bo}/ \rho_{ao}$ = 1.2 and 1.5 for Ca and Ba compounds, respectively. Contrary to CaFe$_{2}$As$_{2}$, BaFe$_{2}$As$_{2}$ reveals an anisotropy in the nominally tetragonal phase, suggesting that either fluctuations play a larger role above $T_{\mathrm{TO}}$ in BaFe$_{2}$As$_{2}$ than in CaFe$_{2}$As$_{2}$, or that there is a higher temperature crossover or phase transition.Comment: extended versio

Identification and characterization of ERV-W-like sequences in Platyrrhini species provides new insights into the evolutionary history of ERV-W in primates

Background: Endogenous Retroviruses (ERVs) constitute approximately 8% of every human genome and are relics of ancestral infections that affected the germ line cells. The ERV-W group contributed to primate physiology by providing an envelope protein (Syncytin-1) that has been adopted for placenta development in hominoids. Expression of Human ERV-W (HERV-W) sequences is investigated for a pathological role in various human diseases. Results: We previously characterized ERV-W group genomic sequences in human and non-human Catarrhini species. We now investigated ERV-W-like sequences in the parvorder Platyrrhini, especially regarding two species with complete genome assemblies, namely marmoset (Callithrix jacchus) and squirrel monkey (Saimiri boliviensis). We identified in both species proviral sequences, annotated as ERV1-1 in respective genome assemblies, sharing high sequence similarities with Catarrhini ERV-W. A total of 130 relatively intact proviruses from the genomes of marmoset and squirrel monkey were characterized regarding their structural and evolutionarily relationships with Catarrhini ERV-W elements. Platyrrhini ERV-W sequences share several structural features with Catarrhini ERV-W elements and are closely related phylogenetically with the latter as well as with other ERV-W-related gammaretrovirus-like ERVs. The ERV-W group colonized Platyrrhini primates of both Callitrichidae and Atelidae lineages, with provirus formations having occurred mostly between 25 and 15 mya. Two LTR subgroups were associated with monophyletic proviral bodies. A pre-gag region appears to be a sequence feature common to the ERV-W group: it harbors a putative intron sequence that is missing in some ERV-W loci, holding a putative ORF as well. The presence of a long pre-gag portion was confirmed among all gammaretroviral ERV analyzed, suggesting a role in the latter biology. It is noteworthy that, contrary to Catarrhini ERV-W, there was no evidence of L1-mediated mobilization for Platyrrhini ERV-W sequences. Conclusions: Our data establish that ERV-W is not exclusive to Catarrhini primates but colonized both parvorders of Simiiformes, providing further insight into the evolution of ERV-W and the colonization of primate genomes

Statistics of a parallel Poynting vector in the auroral zone as a function of altitude using Polar EFI and MFE data and Astrid-2 EMMA data

We study the wave-related (AC) and static (DC) parallel Poynting vector (Poynting energy flux) as a function of altitude in auroral field lines using Polar EFI and MFE data. The study is statistical and contains 5 years of data in the altitude range 5000–30000 km. We verify the low altitude part of the results by comparison with earlier Astrid-2 EMMA Poynting vector statistics at 1000 km altitude. The EMMA data are also used to statistically compensate the Polar results for the missing zonal electric field component. We compare the Poynting vector with previous statistical DMSP satellite data concerning the electron precipitation power. We find that the AC Poynting vector (Alfvén-wave related Poynting vector) is statistically not sufficient to power auroral electron precipitation, although it may, for <i>K<sub>p</sub></i>>2, power 25–50% of it. The statistical AC Poynting vector also has a stepwise transition at <i>R</i>=4 <i>R<sub>E</sub></i>, so that its amplitude increases with increasing altitude. We suggest that this corresponds to Alfvén waves being in Landau resonance with electrons, so that wave-induced electron acceleration takes place at this altitude range, which was earlier named the Alfvén Resonosphere (ARS). The DC Poynting vector is ~3 times larger than electron precipitation and corresponds mainly to ionospheric Joule heating. In the morning sector (02:00–06:00 MLT) we find that the DC Poynting vector has a nontrivial altitude profile such that it decreases by a factor of ~2 when moving upward from 3 to 4 <i>R<sub>E</sub></i> radial distance. In other nightside MLT sectors the altitude profile is more uniform. The morning sector nontrivial altitude profile may be due to divergence of the perpendicular Poynting vector field at <i>R</i>=3–4 <i>R<sub>E</sub></i>. <p><b>Keywords.</b> Magnetospheric physics (Auroral phenomena; Magnetosphere-ionosphere interactions) – Space plasma physics (Wave-particle interactions