39 resultados para Molecular
Resumo:
Projecte de recerca elaborat a partir duna estada a la University of British Columbia, Canad, entre 2010 i 2012 La malaltia d'Alzheimer (MA) representa avui la forma ms comuna de demncia en la poblaci envellida. Malgrat fa 100 anys que va ser descoberta, encara avui no existeix cap tractament preventiu i/o curatiu ni cap agent de diagnstic que permeti valorar quantitativament l'evoluci d'aquesta malaltia. L'objectiu en el que s'emmarca aquest treball s contribuir a aportar solucions al problema de la manca d'agents teraputics i de diagnosi, unvocs i rigorosos, per a la MA. Des del camp de la qumica bioinorgnica s fcil fixar-se en l'excessiva concentraci d'ions Zn(II) i Cu(II) en els cervells de malalts de MA, plantejar-se la seva utilitzaci com a dianes teraputica i, en conseqncia, cercar agents quelants que evitin la formaci de plaques senils o contribueixin a la seva dissoluci. Si b aquest va ser el punt de partida daquest projecte, els mltiples factors implicats en la patognesi de la MA fan que el clssic paradigma d una molcula, una diana limiti la capacitat de la molcula de combatre aquesta malaltia tan complexa. Per tant, un esfor considerable sha dedicat al disseny dagentsmultifuncionals que combatin els mltiples factors que caracteritzen el desenvolupament de la MA. En el present treball shan dissenyat agents multifuncionals inspirats en dos esquelets moleculars ben establers i coneguts en el camp de la qumica medicinal: la tioflavina-T (ThT) i la deferiprona (DFP). La utilitzaci de tcniques in silico que inclouen clculs farmacocintics i modelatge molecular ha estat un procs cabdal per a lavaluaci dels millors candidats en base als segents requeriments: (a) compliment de determinades propietats farmacocintiques que estableixin el seu possible s com a frmac (b) hidrofobicitat adequada per travessar la BBB i (c) interacci amb el pptid Aen soluci.
Resumo:
La meva incorporaci al grup de recerca del Prof. McCammon (University of California San Diego) en qualitat dinvestigador post doctoral amb una beca Beatriu de Pins, va tenir lloc el passat 1 de desembre de 2010; on vaig dur a terme les meves tasques de recerca fins al darrer 1 dabril de 2012. El Prof. McCammon s un referent mundial en laplicaci de simulacions de dinmica molecular (MD) en sistemes biolgics dinters hum. La contribuci ms important del Prof. McCammon en la simulaci de sistemes biolgics s el desenvolupament del mtode de dinmiques moleculars accelerades (AMD). Les simulacions MD convencionals, les quals estan limitades a lescala de temps del nanosegon (~10-9s), no son adients per lestudi de sistemes biolgics rellevants a escales de temps mes llargues (s, ms...). AMD permet explorar fenmens moleculars poc freqents per que son clau per lenteniment de molts sistemes biolgics; fenmens que no podrien ser observats dun altre manera. Durant la meva estada a la University of California San Diego, vaig treballar en diferent aplicacions de les simulacions AMD, incloent fotoqumica i disseny de frmacs per ordinador. Concretament, primer vaig desenvolupar amb xit una combinaci dels mtodes AMD i simulacions Car-Parrinello per millorar lexploraci de camins de desactivaci (interseccions cniques) en reaccions qumiques fotoactivades. En segon lloc, vaig aplicar tcniques estadstiques (Replica Exchange) amb AMD en la descripci dinteraccions protena-lligand. Finalment, vaig dur a terme un estudi de disseny de frmacs per ordinador en la protena-G Rho (involucrada en el desenvolupament de cncer hum) combinant anlisis estructurals i simulacions AMD. Els projectes en els quals he participat han estat publicats (o estan encara en procs de revisi) en diferents revistes cientfiques, i han estat presentats en diferents congressos internacionals. La memria inclosa a continuaci cont ms detalls de cada projecte esmentat.
Resumo:
Descriptors based on Molecular Interaction Fields (MIF) are highly suitable for drug discovery, but their size (thousands of variables) often limits their application in practice. Here we describe a simple and fast computational method that extracts from a MIF a handful of highly informative points (hot spots) which summarize the most relevant information. The method was specifically developed for drug discovery, is fast, and does not require human supervision, being suitable for its application on very large series of compounds. The quality of the results has been tested by running the method on the ligand structure of a large number of ligand-receptor complexes and then comparing the position of the selected hot spots with actual atoms of the receptor. As an additional test, the hot spots obtained with the novel method were used to obtain GRIND-like molecular descriptors which were compared with the original GRIND. In both cases the results show that the novel method is highly suitable for describing ligand-receptor interactions and compares favorably with other state-of-the-art methods.
Resumo:
The information provided by the alignment-independent GRid Independent Descriptors (GRIND) can be condensed by the application of principal component analysis, obtaining a small number of principal properties (GRIND-PP), which is more suitable for describing molecular similarity. The objective of the present study is to optimize diverse parameters involved in the obtention of the GRIND-PP and validate their suitability for applications, requiring a biologically relevant description of the molecular similarity. With this aim, GRIND-PP computed with a collection of diverse settings were used to carry out ligand-based virtual screening (LBVS) on standard conditions. The quality of the results obtained was remarkable and comparable with other LBVS methods, and their detailed statistical analysis allowed to identify the method settings more determinant for the quality of the results and their optimum. Remarkably, some of these optimum settings differ significantly from those used in previously published applications, revealing their unexplored potential. Their applicability in large compound database was also explored by comparing the equivalence of the results obtained using either computed or projected principal properties. In general, the results of the study confirm the suitability of the GRIND-PP for practical applications and provide useful hints about how they should be computed for obtaining optimum results.
Resumo:
The complex etiology of schizophrenia has prompted researchers to develop clozapine-related multitargetstrategies to combat its symptoms. Here we describe a series of new 6-aminomethylbenzofuranones in aneffort to find new chemical structures with balanced affinities for 5-HT2 and dopamine receptors. Throughbiological and computational studies of 5-HT2A and D2 receptors, we identified the receptor serine residuesS3.36 and S5.46 as the molecular keys to explaining the differences in affinity and selectivity betweenthese new compounds for this group of receptors. Specifically, the ability of these compounds to establishone or two H-bonds with these key residues appears to explain their difference in affinity. In addition, wedescribe compound 2 (QF1004B) as a tool to elucidate the role of 5-HT2C receptors in mediating antipsychoticeffects and metabolic adverse events. The compound 16a (QF1018B) showed moderate to high affinitiesfor D2 and 5-HT2A receptors, and a 5-HT2A/D2 ratio was predictive of an atypical antipsychotic profile.
Resumo:
La determinaci de Cr(VI) en laigua per espectroscpia dabsorci molecular a la regi visible es realitza mitjanant una tcnica colorimtrica per reacci amb un reactiu cromognic. El Cr(VI) reacciona amb la 1,5-Difenilcarbacida formant un complex de color vermell-violeta que absorbeix radiaci a la longitud dona de 540 nm. Tradicionalment, la determinaci de Cr(VI) per colorimetria es realitza de forma manual i discontnua, essent un mtode repetitiu i laboris que t implcit un cost de m dobra i de temps considerable, tant pel que es refereix a la preparaci de les mostres i dels patrons, com al propi acte de la mesura a laparell. Aquest projecte sha realitzat sota la idea que les determinacions de Cr(VI) per colorimetria, poden complir els requisits bsics operacionals dels mtodes danlisi de flux en continu. Partint daquesta base, sha desenvolupat un nou equip de mesura per realitzar les determinacions de Cr(VI) amb una presa de mostres automatitzada, i un rgim de treball en continu. Lobjectiu daquest projecte s la posta a punt, automatitzaci, i validaci de la tcnica danlisi instrumental de determinaci de crom (VI) en continu per espectroscpia molecular visible
Resumo:
Shan descrit informes contradictoris sobre els efectes dEfavirenz (EFV) i lopinavir/ritonavir (LPV/r) al teixit adips subcutani (SAT). Lobjectiu daquest estudi era evaluar els efectes moleculars i clnics de LPV/r i EFV, tots dos en combinaci amb tenofovir/emtricitabina (TDF/FTC), sobre el SAT dels pacients infectats per VIH sense tractament antirretroviral previ. Desprs de 48 setmanes de tractament, TDF/FTC ms LPV/r va augmentar de forma significativa el greix de les extremitats i els parmetres lipdics, mentre que TDF/FTC/EFV noms va augmentar de forma significativa el colesterol total i LDL. La expressi dels gens implicats en la diferenciaci dels adipcits i dels gens relacionats amb la mitocondria no va canviar de forma significativa en el SAT dels pacients exposats a LPV/r, mentre que Cyt b i els gens relacionats amb la imflamaci estaven estimulats de forma significativa en el SAT dels pacients exposats a EFV.
Resumo:
El projecte en el qual semmarca aquest treball de recerca es centra en el desenvolupament dinterruptors moleculars que permeten el control del funcionament dun canal inic de les cllules del sistema nervis central. En aquest treball de Mster en Experimentaci Qumica, sha treballat, ms concretament, en la sntesi del derivat del glutamat. Sha dissenyat i desenvolupat una ruta sinttica del fragment de glutamat en 8 passos amb un 7% de rendiment global.
Resumo:
A polarizable quantum mechanics and molecular mechanics model has been extended to account for the difference between the macroscopic electric field and the actual electric field felt by the solute molecule. This enables the calculation of effective microscopic properties which can be related to macroscopic susceptibilities directly comparable with experimental results. By seperating the discrete local field into two distinct contribution we define two different microscopic properties, the so-called solute and effective properties. The solute properties account for the pure solvent effects, i.e., effects even when the macroscopic electric field is zero, and the effective properties account for both the pure solvent effects and the effect from the induced dipoles in the solvent due to the macroscopic electric field. We present results for the linear and nonlinear polarizabilities of water and acetonitrile both in the gas phase and in the liquid phase. For all the properties we find that the pure solvent effect increases the properties whereas the induced electric field decreases the properties. Furthermore, we present results for the refractive index, third-harmonic generation (THG), and electric field induced second-harmonic generation (EFISH) for liquid water and acetonitrile. We find in general good agreement between the calculated and experimental results for the refractive index and the THG susceptibility. For the EFISH susceptibility, however, the difference between experiment and theory is larger since the orientational effect arising from the static electric field is not accurately described
