Estrella Lozoya

MEPSIM: A computational package for analysis and comparison of molecular electrostatic potentials

SummaryMEPSIM is a computational system which allows an integrated computation, analysis, and comparison of molecular electrostatic potential (MEP) distributions. It includes several modules. Module MEPPLA supplies MEP values for the points of a grid defined on a plane which is specified by a set of three points. The results of this program can easily be converted into MEP maps using third-parties graphical software. Module MEPMIN allows to find automatically the MEP minima of a molecular system. It supplies the cartesian coordinates of these minima, their values, and all the geometrical relationships between them (distances, angles, and dihedral angles). Module MEPCOMP computes a similarity coefficient between the MEP distributions of two molecules and finds their relative position that maximizes the similarity. Module MEPCONF performs the same process as MEPCOMP, considering not only the relative position of both molecules but also a conformational degree of freedom of one of them. The most recently developed module, MEPPAR, is another modification of MEPCOMP in order to compute the MEP similarity between two molecules, but only taking into account a particular plane. The latter module is particularly useful to compare MEP distributions generated by π systems of aromatic rings. MEPSIM can use several wavefunction computation approaches to obtain MEP distributions. MEPSIM has a menu type interface to simplify the following tasks: creation of input files from output files of external programs (GAUSSIAN and AMPAC/MOPAC), setting the parameters for the current computation, and submitting jobs to the batch queues of the computer. MEPSIM has been coded in FORTRAN and its current version runs on VMS/VAX computers.

Maximum electrostatic similarity between biomolecules optimizing both relative positions and conformations

Abstract Software was developed to find automatically the maximum electrostatic similarity between biomolecules by varying the relative positions and the conformations of one of them. This similarity is defined by means of the Spearman correlation coefficient computed over the molecular electrostatic potential (MEP) values at points of a volume around the molecules. Several tests are presented, including a comparison between 1-methyl-4-phenyl-1,2,5,6-tetrahydropyridine (MPTP) and benzylamine (BZA), two substrates of monoamine oxidase B (MAO-B). The proposed algorithm can be useful for molecular modelling and quantitative structure-activity relationship (QSAR) studies.

Efficient method for the preparation of (S)-5-hydroxynorvaline

Abstract ( S )-5-Hydroxynorvaline 4 has been prepared from l -glutamic acid 1 by simultaneous protection of the α-amino and α-carboxyl groups, and selective reduction of the resulting boroxazolidone 2 . This method is rapid and highly reproducible, and gives very pure ( S )-5-hydroxynorvaline after simple anion-exchange purification. It improves existing methods by providing a purer product in higher yields.

Structure-activity relationships (SAR) and structure-kinetic relationships (SKR) of bicyclic heteroaromatic acetic acids as potent CRTh2 antagonists III: the role of a hydrogen-bond acceptor in long receptor residence times.

The correct positioning and orientation of an hydrogen bond acceptor (HBA) in the tail portion of the biaryl series of CRTh2 antagonists is a requirement for long receptor residence time. The HBA in combination with a small steric substituent in the core section (R(core) ≠ H) gives access to compounds with dissociation half-lives of ⩾ 24h.

Biaryl analogues of teriflunomide as potent DHODH inhibitors.

The structure-activity relationships of a novel series of biaryl dihydroorotate dehydrogenase (DHODH) inhibitors related to teriflunomide are disclosed. These biaryl derivatives were the result of structure-based design and proved to be potent DHODH inhibitors which in addition showed good antiproliferative activities on peripheral blood mononuclear cells and good efficacies in vivo in the rat adjuvant-induced-arthritis model.

Application of a phenotypic drug discovery strategy to identify biological and chemical starting points for inhibition of TSLP production in lung epithelial cells

Thymic stromal lymphopoietin (TSLP) is a cytokine released by human lung epithelium in response to external insult. Considered as a master switch in T helper 2 lymphocyte (Th2) mediated responses, TSLP is believed to play a key role in allergic diseases including asthma. The aim of this study was to use a phenotypic approach to identify new biological and chemical starting points for inhibition of TSLP production in human bronchial epithelial cells (NHBE), with the objective of reducing Th2-mediated airway inflammation. To this end, a phenotypic screen was performed using poly I:C / IL-4 stimulated NHBE cells interrogated with a 44,974 compound library. As a result, 85 hits which downregulated TSLP protein and mRNA levels were identified and a representative subset of 7 hits was selected for further characterization. These molecules inhibited the activity of several members of the MAPK, PI3K and tyrosine kinase families and some of them have been reported as modulators of cellular phenotypic endpoints like cell-cell contacts, microtubule polymerization and caspase activation. Characterization of the biological profile of the hits suggested that mTOR could be a key activity involved in the regulation of TSLP production in NHBE cells. Among other targeted kinases, inhibition of p38 MAPK and JAK kinases showed different degrees of correlation with TSLP downregulation, while Syk kinase did not seem to be related. Overall, inhibition of TSLP production by the selected hits, rather than resulting from inhibition of single isolated targets, appeared to be due to a combination of activities with different levels of relevance. Finally, a hit expansion exercise yielded additional active compounds that could be amenable to further optimization, providing an opportunity to dissociate TSLP inhibition from other non-desired activities. This study illustrates the potential of phenotypic drug discovery to complement target based approaches by providing new chemistry and biology leads.

Modelling of the 5-HT2A Receptor and Its Ligand Complexes

Up to now, modelling of the GPCR is one of the most interesting but most difficult challenges in protein modelling. The difficulties arise from the lack of crystallographic data to be used in a standard homology approach. The first GPCR models that were published were based in the crystallographic data of bacteriorhodopsin, which is an inappropriate template because it is not a GPCR and it shows a very low homology degree with the GPCRs. More recently, a low resolution electron density map of rodhopsin1 is being used for the packing of the GPCR transmembrane helices (TMH). This history reflects the constant need of ameliorating the existing models by taking into account new experimental data or improved theoretical or computational tools.