Biological evaluation, molecular docking and DFT calculations of pyrrole-based derivatives as dual acting AChE/MAO-B inhibitors

Considering the complex pathophysiology of Alzheimer’s disease (AD), the multitarget ligand strategy is expected to provide superior effects for the treatment of the neurological disease compared to the classic single target strategy. Thus, six pyrrole-based compounds were evaluated for their dual monoamine oxidase type B (MAO-B) and acetylcholinesterase (AChE) inhibitory capacities. Most of the compounds revealed good AChE activities at 10 µM concentrations. 5d most potently inhibited AChE with 75%, while the hydrazide 5 demonstrated blocking effect of 51% at 10 µM concentrations. However, limited MAO-B inhibitory effects were observed with the exception of compounds 3, and especially 5 (30% inhibition at 1 µM). The in vitro assessments showed that the unsubstituted pyrrole-based hydrazide 5 is the best dual inhibitor of MAO-B/AChE enzymes. Subsequent in silico molecular docking simulations of 5 in the active sites of MAO-B (2V5Z) and AChE (4EY6) displayed the formation of stable enzyme-ligand complexes. To rationalize the biological assays, density functional theory (DFT) calculations were carried out at the B3LYP/6-311++(d,p) level of theory. Overall, the results demonstrated that the pyrrole-based hydrazide 5 is a dual-acting AchE/MAO-B inhibitor with good antioxidant properties, which could be considered as a candidate for future lead-optimizations

DATABASE ENRICHMENTS OF MAO-B THROUGH ENSEMBLE DOCKING

Objective: The recent growth of highly resoluted crystallographic structures, together with the continuous improvements of the computing power, has established molecular docking as a leading drug design technique. However, the problems concerning the receptor flexibility and the lowered ability of docking software to correctly score the occurred interactions in some receptors are still relevant. Methods: Recently, several research groups have reported an enhancement in enrichment values when ensemble docking has been applied. Therefore, we utilized the latest technique for a dataset of Monoamine Oxidase–B (MAO-B) inhibitors. The docking program GOLD 5.3 was used in our study. Several docking parameters (grid space, scoring functions and ligand flexibility) were altered in order to achieve the optimal docking protocol. Results: The results of 200 000+docking simulations are represented in a modest table. The ensembled simulations demonstrated low ability of the docking software to correctly score the actives seeded in the dataset. However, the superimposed complex-1S3B-1OJA-1OJC, achieved a moderate enrichment value equaled to 9. No significant improvements were noted when five complexed receptors were employed. Conclusion: As a conclusion, it should be noted that in some cases the ensemble docking enhanced the database enrichments, however overall the value is not suitable for future virtual screening. Further investigations in that area should be considered

Measurement of the t-channel single top quark production cross section in pp collisions at √s =7 TeV

Peer reviewe

Calibration of the CMS Drift Tube Chambers and Measurement of the Drift Velocity with Cosmic Rays

Peer reviewe

Aligning the CMS Muon Chambers with the Muon Alignment System during an Extended Cosmic Ray Run

Peer reviewe

Measurement of B(B)over-bar angular correlations based on secondary vertex reconstruction at √s =7 TeV

This is the pre-print version of the Published Article, which can be accessed from the link below - Copyright @ 2011 Springer VerlagA measurement of the angular correlations between beauty and anti-beauty hadrons (B B-bar) produced in pp collisions at a centre-of-mass energy of 7 TeV at the CERN LHC is presented, probing for the first time the region of small angular separation. The B hadrons are identified by the presence of displaced secondary vertices from their decays. The B hadron angular separation is reconstructed from the decay vertices and the primary-interaction vertex. The differential B B-bar production cross section, measured from a data sample collected by CMS and corresponding to an integrated luminosity of 3.1 inverse picobarns, shows that a sizable fraction of the B B-bar pairs are produced with small opening angles. These studies provide a test of QCD and further insight into the dynamics of b b-bar production

Precise mapping of the magnetic field in the CMS barrel yoke using cosmic rays

This is the Pre-print version of the Article. The official published version can be accessed from the link below - Copyright @ 2010 IOPThe CMS detector is designed around a large 4 T superconducting solenoid, enclosed in a 12 000-tonne steel return yoke. A detailed map of the magnetic field is required for the accurate simulation and reconstruction of physics events in the CMS detector, not only in the inner tracking region inside the solenoid but also in the large and complex structure of the steel yoke, which is instrumented with muon chambers. Using a large sample of cosmic muon events collected by CMS in 2008, the field in the steel of the barrel yoke has been determined with a precision of 3 to 8% depending on the location.This work is supported by FMSR (Austria); FNRS and FWO (Belgium); CNPq, CAPES, FAPERJ, and FAPESP (Brazil); MES (Bulgaria); CERN; CAS, MoST, and NSFC (China); COLCIENCIAS (Colombia); MSES (Croatia); RPF (Cyprus); Academy of Sciences and NICPB (Estonia); Academy of Finland, ME, and HIP (Finland); CEA and CNRS/IN2P3 (France); BMBF, DFG, and HGF (Germany); GSRT (Greece); OTKA and NKTH (Hungary); DAE and DST (India); IPM (Iran); SFI (Ireland); INFN (Italy); NRF (Korea); LAS (Lithuania); CINVESTAV, CONACYT, SEP, and UASLP-FAI (Mexico); PAEC (Pakistan); SCSR (Poland); FCT (Portugal); JINR (Armenia, Belarus, Georgia, Ukraine, Uzbekistan); MST and MAE (Russia); MSTDS (Serbia); MICINN and CPAN (Spain); Swiss Funding Agencies (Switzerland); NSC (Taipei); TUBITAK and TAEK (Turkey); STFC (United Kingdom); DOE and NSF (USA)

Search for a WbosondecayingtoamuonandaneutrinoinW^ boson decaying to a muon and a neutrino in ppcollisionsat collisions at s = 7$ TeV

A new heavy gauge boson, W′, decaying to a muon and a neutrino, is searched for in pp collisions at a centre-of-mass energy of 7 TeV. The data, collected with the CMS detector at the LHC, correspond to an integrated luminosity of 36 pb−1. No significant excess of events above the standard model expectation is found in the transverse mass distribution of the muon–neutrino system. Masses below 1.40 TeV are excluded at the 95% confidence level for a sequential standard-model-like W′. The W′ mass lower limit increases to 1.58 TeV when the present analysis is combined with the CMS result for the electron channe

Discutindo a educação ambiental no cotidiano escolar: desenvolvimento de projetos na escola formação inicial e continuada de professores

A presente pesquisa buscou discutir como a Educação Ambiental (EA) vem sendo trabalhada, no Ensino Fundamental e como os docentes desta escola compreendem e vem inserindo a EA no cotidiano escolar., em uma escola estadual do município de Tangará da Serra/MT, Brasil. Para tanto, realizou-se entrevistas com os professores que fazem parte de um projeto interdisciplinar de EA na escola pesquisada. Verificou-se que o projeto da escola não vem conseguindo alcançar os objetivos propostos por: desconhecimento do mesmo, pelos professores; formação deficiente dos professores, não entendimento da EA como processo de ensino-aprendizagem, falta de recursos didáticos, planejamento inadequado das atividades. A partir dessa constatação, procurou-se debater a impossibilidade de tratar do tema fora do trabalho interdisciplinar, bem como, e principalmente, a importância de um estudo mais aprofundado de EA, vinculando teoria e prática, tanto na formação docente, como em projetos escolares, a fim de fugir do tradicional vínculo “EA e ecologia, lixo e horta”.Facultad de Humanidades y Ciencias de la Educació

Suitable Docking Protocol for the Design of Novel Coumarin Derivatives with Selective MAO-B Effects

Recently, the application of molecular docking is drastically increasing due to the rapid growth of resolved crystallographic receptors with co-crystallized ligands. However, the inability of docking softwares to correctly score the occurred interactions between ligands and receptors is still a relevant issue. This study examined the Pearson’s correlation coefficient between the experimental monoamine oxidase-B (MAO-B) inhibitory activity of 44 novel coumarins and the obtained GOLD 5.3 docking scores. Subsequently, optimization of the docking protocol was carried out to achieve the best possible pairwise correlation. Numerous modifications in the docking settings such as alteration in the scoring functions, size of the grid space, presence of active waters, and side-chain flexibility were conducted. Furthermore, ensemble docking simulations into two superimposed complexes were performed. The model was validated with a test set. A significant Pearson’s correlation coefficient of 0.8217 was obtained for the latter. In the final stage of our work, we observed the major interactions between the top-scored ligands and the active site of 1S3B