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M Orozco

Publications and source records attributed to M Orozco.

At least 37 records · Page 2Linked to original sources
PubMed2000

Synthesis of enantiopure trans-3,4-disubstituted piperidines. An enantiodivergent synthesis of (+)- and (-)-paroxetine.

Reaction of (R)-phenylglycinol with methyl 5-oxopentanoate gave either bicyclic lactam cis-1 (the kinetic product) or its isomer trans-1 (under equilibrating conditions) as the major products, which were converted to the corresponding (cis or trans) unsaturated lactams 4 and 5. On treatment with lithium alkyl (or aryl) cyanocuprates, these chiral building blocks undergo conjugate addition to give enantiopure trans-3,4-substituted 2-piperidone derivatives in high yield and stereoselectivity. The synthetic potential of this transformation is illustrated by the synthesis of (+)-femoxetine and the two enantiomers of the known antidepressant paroxetine.

Antidepressive Agents, Second-Generation↗
PubMed2000

Mixed QM/MM molecular electrostatic potentials.

A new method is presented for the calculation of the Molecular Electrostatic Potential (MEP) in large systems. Based on the mixed Quantum Mechanics/Molecular Mechanics (QM/MM) approach, the method assumes both a quantum and classical description for the molecule, and the calculation of the MEP in the space surrounding the molecule is made using this dual treatment. The MEP at points close to the molecule is computed using a full QM formalism, while a pure classical evaluation of the MEP is used for points located at large distances from the molecule. The algorithm allows the user to select the desired level of accuracy in the MEP, so that the definition of the regions where the MEP is computed at the classical or QM levels is adjusted automatically. The potential use of this QM/MM MEP in molecular modeling studies is discussed.

Algorithms↗
PubMed2000

Glutaryl-CoA dehydrogenase deficiency in Spain: evidence of two groups of patients, genetically, and biochemically distinct.

Glutaryl-CoA dehydrogenase (GCDH) deficiency causes glutaric aciduria type I (GA I), an inborn error of metabolism that is characterized clinically by dystonia and dyskinesia and pathologically by neural degeneration of the caudate and putamen. Studies of metabolite excretion allowed us to categorize 43 GA I Spanish patients into two groups: group 1 (26 patients), those presenting with high excretion of both glutarate and 3-hydroxyglutarate, and group 2 (17 patients), those who might not be detected by routine urine organic acid analysis because glutarate might be normal and 3-hydroxyglutarate only slightly higher than controls. Single-strand conformation polymorphism (SSCP) screening and sequence analysis of the 11 exons and the corresponding intron boundaries of the GCDH gene allowed us to identify 13 novel and 10 previously described mutations. The most frequent mutations in group 1 were A293T and R402W with an allele frequency of 30% and 28%, respectively. These two mutations were also found in group 2, but always in heterozygosity, in particular in combination with mutations V400M or R227P. Interestingly, mutations V400M and R227P were only found in group 2, and at least one of these mutations was found in 11 of 15 unrelated alleles, accounting together for 53% of the mutant alleles in group 2. Therefore, it seems clear that two genetically and biochemically distinct groups of patients exist. The severity of the clinical phenotype seems to be closely linked to the development of encephalopathic crises rather than to residual enzyme activity or genotype. Comparison of GCDH protein with other acyl-CoA dehydrogenases (whose x-ray crystal structure has been determined) reveals that most of the mutations identified in GCDH protein seem to affect folding and tetramerization, as has been described for a number of mutations affecting mitochondrial beta-oxidation acyl-CoA dehydrogenases.

Alleles↗
PubMed1999

Predicting relative binding free energies of tacrine-huperzine A hybrids as inhibitors of acetylcholinesterase.

The binding of the 9-methyl derivative of tacrine-huperzine A hybrid to Torpedo californica acetylcholinesterase (AChE) has been studied by computational methods. Molecular dynamics simulations have been performed for the AChE-drug complex considering two different ionization states of the protein and two different orientations of the drug in the binding pocket, which were chosen from a previous screening procedure. Analysis of structural fluctuations and of the pattern of interactions between drug and enzyme clearly favor one binding mode for the tacrine-huperzine A hydrid, which mixes effectively some of the binding features of tacrine and huperzine A. The differences in inhibitory activity for a series of related derivatives have been successfully predicted by free energy calculations, which reinforces the confidence in the binding mode and its usefulness for molecular modeling studies. The same techniques have been used to make de novo predictions for a new 3-fluoro-9-ethyl derivative, which can be used to verify a posteriori the goodness of the binding mode. Finally, we have also investigated the effect of replacing Phe300 in the Torpedo californica enzyme by Tyr, which is present in the human AChE. The results indicate that the Phe330-->Tyr mutation is expected to have little effect on the binding affinities. Overall, the whole of results supports the validity of the putative binding model to explain the binding of tacrine-huperzine A hybrids to AChE.

Acetylcholinesterase↗
PubMed1999

Synthesis, in vitro pharmacology, and molecular modeling of very potent tacrine-huperzine A hybrids as acetylcholinesterase inhibitors of potential interest for the treatment of Alzheimer's disease.

Eleven new 12-amino-6,7,10,11-tetrahydro-7, 11-methanocycloocta[b]quinoline derivatives [tacrine (THA)-huperzine A hybrids, rac-21-31] have been synthesized as racemic mixtures and tested as acetylcholinesterase (AChE) inhibitors. For derivatives unsubstituted at the benzene ring, the highest activity was obtained for the 9-ethyl derivative rac-20, previously prepared by our group. More bulky substituents at position 9 led to less active compounds, although some of them [9-isopropyl (rac-22), 9-allyl (rac-23), and 9-phenyl (rac-26)] show activities similar to that of THA. Substitution at position 1 or 3 with methyl or fluorine atoms always led to more active compounds. Among them, the highest activity was observed for the 3-fluoro-9-methyl derivative rac-28 [about 15-fold more active than THA and about 9-fold more active than (-)-huperzine A]. The activity of some THA-huperzine A hybrids (rac-19, rac-20, rac-28, and rac-30), which were separated into their enantiomers by chiral medium-pressure liquid chromatography (chiral MPLC), using microcrystalline cellulose triacetate as the chiral stationary phase, showed the eutomer to be always the levorotatory enantiomer, their activity being roughly double that of the corresponding racemic mixture, the distomer being much less active. Also, the activity of some of these compounds inhibiting butyrylcholinesterase (BChE) was tested. Most of them [rac-27-31, (-)-28, and (-)-30], which are more active than (-)-huperzine A as AChE inhibitors, turned out to be quite selective for AChE, although not so selective as (-)-huperzine A. Most of the tested compounds 19-31 proved to be much more active than THA in reversing the neuromuscular blockade induced by d-tubocurarine. Molecular modeling of the interaction of these compounds with AChE from Torpedo californica showed them to interact as truly THA-huperzine A hybrids: the 4-aminoquinoline subunit of (-)-19 occupies the same position of the corresponding subunit in THA, while its bicyclo[3.3.1]nonadiene substructure roughly occupies the same position of the corresponding substructure in (-)-huperzine A, in agreement with the absolute configurations of (-)-19 and (-)-huperzine A.

Acetylcholinesterase↗
PubMed1999

Can G-C Hoogsteen-wobble pairs contribute to the stability of d(G. C-C) triplexes?

Quantum mechanics, molecular dynamics and statistical mechanics methods are used to analyze the importance of neutral Hoogsteen-wobble G.C pairing in the stabilization of triple helices based on the poly-(G.C-C) trio at neutral pH and low ionic strength. In spite of the existence of a single hydrogen bond, the Hoogsteen-wobble G.C pair is found to be quite stable both in gas phase and solvated DNA. Molecular dynamics simulations of different triplexes based on the d(G.C-C) trio leads to stable structures if the neutral d(G.C-C) steps stabilized by Hoogsteen-wobble pairs are mixed with d(G.C-C+) steps. Finally, high level ab initio calculations and thermodynamic integration techniques are used to determine the relative stability of G.C wobble and G.C imino pairings. It is found that triplexes containing the imino pairing are slightly more stable structures than those with the wobble one, due mainly to a better stacking.

Base Pairing↗
PubMed1999

Theoretical calculations, synthesis and base pairing properties of oligonucleotides containing 8-amino-2'-deoxyadenosine.

Theoretical calculations on double and triple helices containing 8-amino-2'-deoxyadenosine were made to analyze the possible differences in base pairing properties between 8-aminoadenine and adenine. These calculations indicate a strong preferential stabilization of the triplex over the duplex when adenine is replaced by 8-aminoadenine. In addition, a protected phosphoramidite derivative of 8-amino-2'-deoxyadenosine was prepared for the introduction of 8-aminoadenine into synthetic oligonucleotides using the phosphite-triester approach. DNA triple helical structures are normally observed at acidic pH. However, when oligonucleotides carrying 8-aminoadenine are used, very stable triple helical structures can be observed even at neutral pH. Biological applications of triple helices could benefit from the use of 8-aminoadenine derivatives.

Chromatography, High Pressure Liquid↗
PubMed1999

Fractional description of free energies of solvation.

A new and rigorous method for the fractional description of solvation and transfer free energies is presented. The method is based on the use of the Miertus-Scrocco-Tomasi self-consistent reaction field method (MST-SCRF), and allows for a rigorous partition of the total solvation free energy into surface elements. The method gives a complete picture of the hydrophobicity/hydrophilicity of molecules. Present results allow us to expect that the method might provide useful information in drug design and molecular modeling studies.

Benzene Derivatives↗
PubMed1999

Role of sugar re-puckering in the transition of A and B forms of DNA in solution. A molecular dynamics study.

State of the art molecular dynamic simulations show that simple modification of the sugar puckering of 2'deoxyriboses leads to a reversible change between two stable forms of DNA which resemble very closely the canonical A and B duplex forms. Analysis of the A-type and B-type structures reveals interesting, and previously unknown features of these two families of conformations of the DNA.

Carbohydrates↗
PubMed1998

The GAGA factor of Drosophila binds triple-stranded DNA.

The Drosophila GAGA factor binds specifically to simple repeating d(GA.TC)n DNA sequences. These sequences are known to be capable of forming triple-stranded DNA as well as other non-B-DNA conformations. Here, it is shown that GAGA binds to a d[CT(GA.TC)]22 intermolecular triplex with similar specificity and affinity as to a regular double-stranded B-form d(GA.TC)22 sequence. The interaction of GAGA with triplex DNA cannot, however, stimulate transcription in vitro. The affinity of GAGA for triplexes of the purine motif, such as a d[AG(GA.TC)]22 intermolecular triplex, is significantly lower. The DNA binding domain of GAGA is sufficient for efficient binding to triplex DNA. Based on the reported solution structure of the complex of GAGA-DNA binding domain with double-stranded DNA, a model for its interaction with triplex DNA is proposed in which most of the protein-DNA contacts observed in duplex DNA are maintained, especially those occurring through the minor groove. The higher negative charge of the triplex is likely to have also an important contribution to both the specificity and affinity of the interaction.

Animals↗
PubMed1998

Salt bridge interactions: stability of the ionic and neutral complexes in the gas phase, in solution, and in proteins.

A theoretical study on the stability of the salt bridges in the gas phase, in solution, and in the interior of proteins is presented. The study is mainly focused on the interaction between acetate and methylguanidinium ions, which were used as model compounds for the salt bridge between Asp (Glu) and Arg. Two different solvents (water and chloroform) were used to analyze the effect of varying the dielectric constant of the surrounding media on the salt bridge interaction. Calculations in protein environments were performed by using a set of selected protein crystal structures. In all cases attention was paid to the difference in stability between the ion pair and neutral hydrogen-bonded forms. Comparison of the results determined in the gas phase and in solution allows us to stress the large influence of the environment on the binding process, as well as on the relative stability between the ionic and neutral complexes. The high anisotropy of proteins and the local microenvironment in the interior of proteins make a decisive contribution in modulating the energetics of the salt bridge. In general, the formation of salt bridges in proteins is not particularly favored, with the ion pair structure being preferred over the interaction between neutral species.

Acetates↗
PubMed1998

On the potential role of the amino nitrogen atom as a hydrogen bond acceptor in macromolecules.

Crystallographic studies of duplex DNA have indicated that opposing exocyclic amino groups may form close NH⋯:N contacts. To study the nature of such interactions, we have examined the database of small molecule, high-resolution crystal structures for more accurate examples of this type of unconventional interaction. We have found cases where the amino groups in guanine and adenine bases accept hydrogen bonds from conventional donors, such as amino or hydroxyl groups. More frequently, the purine amino group was found to contact closely electropositive C-H groups. Searches of the nucleic acid structural databases also yielded several examples where the purine amino group is contacted by hydrogen bond donors in macromolecules. Ab initio calculations indicate that the hydrogen-amino contact is improved energetically when the amino group moves from the conventional geometry, where all atoms are co-planar with the base, to one in which the hydrogen atoms lie out of the plane and the nitrogen is at the apex of a pyramid, resulting in polarization of the amino group. The combined structural and theoretical data suggest that the amino group is flexible, and can accommodate close contacts, because the resulting polarization permits electropositive atoms to approach the amino group nitrogen more closely than expected for their conventional van der Waals radii. The flexibility of the amino group may permit particular DNA conformations that enforce hydrogen-amino contacts to optimize favorable stacking interactions, and it may play a role in the recognition of nucleosides. We speculate that the amino group can accept hydrogen bonds under special circumstances in macromolecules, and that this ability might play a mechanistic role in catalytic processes such as deamination or amino transfer.

Crystallography↗
PubMed1998

Is polarization important in cation-pi interactions?

The importance of cation->aromatic polarization effects on cation-pi interactions has been explored. Theoretical calculations demonstrate that polarization is a large contribution to cation-aromatic interactions, and particularly to cation-pi interactions. For a series of compounds with a similar aromatic core, polarization is constant and makes small influence in the relative cation-binding energies. However, when the aromatic core changes polarization contributions might be very different. We found that the generalized molecular interaction potential with polarization is a very fast and powerful tool for the prediction of cation binding of aromatic compounds.

Journal Article↗
PubMed1998

A scale without anthropometric measurements can be used to identify low weight-for-age in children less than five years old.

Malnutrition and morbidity have a synergistic association that often leads to death. However, malnutrition in children who die is largely underreported, because anthropometry of the deceased child is rarely known. This study had two purposes: i) to develop a scale that would help determine if a child had low weight-for-age (w/a), in the absence of anthropometric measures; and ii) to select an appropriate cut-off that would give the best sensitivity (Se) and specificity (Sp) of the proposed scale when contrasted with actual w/a measurement. The study was designed as a diagnostic test, and carried out in a rural area in central Mexico. We included 132 children under 5 y old with w/a under -2 Z score and 284 children with marginal or no w/a deficit as a control group. The proposed scale included potential predictive variables from clinical, socioeconomic and family factors. The best logistic regression model to predict low w/a included: birth weight less than 2,800 g, introduction of weaning foods after the sixth month of life, introduction of animal protein after the sixth month of life, low socioeconomic status, low w/a in siblings and more than three morbidity episodes in the previous 6 mon. Selecting a cut-off of 4 for this model to identify children with low w/a showed a Se and Sp of 85 and 95%, respectively. We tested the external validity of the scale in a different locale, and included 877 children under 5 y old from 10 rural communities. In this population, the scale showed Se of 84% and Sp of 81% to identify low w/a. Based on these results, we propose that the scale be included as a means of identifying low w/a in children who have died. We believe that this should be done in verbal autopsies, which, based on our previous research, the Ministry of Health adopted as part of the regular activities to monitor problems in the disease to health-seeking to death process.

Birth Weight↗
PubMed1997

Molecular dynamics simulations of the unfolding of barnase in water and 8 M aqueous urea.

Molecular dynamics simulations of barnase have been conducted both in water and in 8 M urea solution for 500 ps at 25 degrees C and for 2000 ps at 85 degrees C. The final structure of the aqueous simulation at room temperature matches closely the structure obtained by NMR and the experimentally observed protections from isotopic exchange. The comparison of the structures generated by the aqueous simulation at 85 degrees C reveals a trajectory composed of groups of geometrically related structures separated by narrow regions of rapid change in structure. The first of these regions displays changes in backbone rmsd to the crystal structure and solvent-accessible area suggestive of a transition state, while the properties observed during the final 300 ps of the simulation are consistent with a stable intermediate. These assignments were confirmed by calculation of the "progress along the reaction coordinate" phi-values using an empirical equation based on a linear response method. The pathway of unfolding defined in this fashion agrees well with the experimental results of site-directed mutagenesis in terms of secondary structure content of the transition state and the intermediate and reproduces the relative stability of the different elements of secondary structure. The results of the simulations in urea suggest a mechanism at the molecular level for its well-known enhancement of the denaturation of proteins. The analysis of radial distribution functions shows that the first solvation shell of the protein is enriched in urea relative to the bulk solvent. The displacement of water molecules allows greater exposure of hydrophobic side chains, as witnessed particularly in the analysis of solvent-accessible surface areas at the higher temperature. Almost all urea molecules in the first shell form at least one hydrogen bond with the protein. They provide a more favorable environment for accommodation of the remaining water molecules, and they facilitate the separation of secondary structure elements by acting as a bridge between groups previously forming intraprotein hydrogen bonds.

Bacterial Proteins↗
PubMed1997

Delayed extradural hematoma after mild head injury: report of three cases.

BACKGROUND: Extradural hematoma has been classically considered to be an acute complication of head injury whose maximum development takes place in the minutes following trauma. Delayed extradural hematoma (DEH) is defined on the basis of an exclusively radiologic criterion: epidural hematoma that is not present in the first neuroradiologic examination made after trauma but that appears in sequential neuroradiologic examinations during patient evolution. This is an infrequent complication that usually appears in hypotensive multiple trauma patients or is related to severe head injury with other intracranial lesions. CASE DESCRIPTION: We present three cases of DEH after mild head injury (GCS > 12) without associated intracranial or traumatic systemic lesions. Therefore, those usually considered to be "protective mechanisms" responsible for delayed development of an extradural hematoma were absent in our three patients. Diagnosis was attained by means of repetition of cranial computed tomography (CT) scan after neurologic impairment was noted. Surgical evacuation of DEH was immediately performed after diagnosis. Postoperative outcome was favorable in two patients who suffered DEH in the supratentorial compartment. One patient who presented a posterior fossa DEH died 3 days after surgery. CONCLUSIONS: Early diagnosis and immediate treatment have proved to be essential for improving the prognosis of patients affected by DEH. Hospital admission under neurologic observation is recommended for patients who have sustained mild head injury associated with those factors that are related to the development of DEH, including GCS score under 15 or the detection of a skull fracture. Normality of a CT scan does not rule out subsequent appearance of delayed traumatic lesions.

Adolescent↗
PubMed1997

Role of tautomerism of 2-azaadenine and 2-azahypoxanthine in substrate recognition by xanthine oxidase.

The tautomerism of 2-azaadenine and 2-hypoxanthine has been examined in the gas phase and in aqueous solution. The tautomerism in the gas phase has been studied by means of semiempirical and ab initio quantum-mechanical computations, as well as density-functional calculations. The influence of the aqueous solvent on the relative stability between tautomers has been estimated from self-consistent reaction field calculations performed with different high-level continuum models. The results provide a detailed picture of the tautomeric preference for these purine bases. The importance of tautomerism in the substrate recognition by xanthine oxidase is discussed. Finally, the rate of oxidation of 2-azaadenine and 2-hypoxanthine by xanthine oxidase is discussed in terms of the recognition model at the enzyme active site.

Adenine↗