Biomedical subjects

I Alkorta

Publications and source records attributed to I Alkorta.

25 records · Page 2Linked to original sources

PubMed1993

Strategies for indirect computer-aided drug design.

This review is intended to describe some of the methods and procedures used for computer-aided drug design when the structure of the macromolecular target is unknown, as is the case for CNS active drugs. Strategies and methods used in computer-aided design of drugs in such instances must be "indirect," i.e., focusing on the characterization of the ligands themselves. This situation is different from one in which the three-dimensional structure of the macromolecular target for a drug is known, for example, for drugs that are enzyme inhibitors, allowing "direct" characterization of ligand-receptor interactions. Two qualitatively different "indirect" approaches are described here. One, called 2D-QSAR, is briefly reviewed. It is based on delineating regression relationships between a specified biological end point and properties of the compounds eliciting it. The other, based on pharmacophore development, constitutes the main part of this review. Several levels of pharmacophore development are described, which differ in the extent to which they encompass fundamental molecular properties that are determinants of receptor recognition and activation. The strengths and limitations of each procedure are discussed and illustrated by examples. Two methods for obtaining model receptor structures are then briefly described. Both rely on the prior success of the indirect methods in obtaining ligand properties that modulate receptor recognition and activation. These emerging capabilities have the potential to bridge the gap between indirect and direct methods of drug design, since, if successful, the design process can continue in a direct mode using explicit characterization of drug-receptor interactions. Strategies for hypothesis validation and use of hypothesis for drug design and discovery are also briefly reviewed. The final sections of this review describe specific computational tools such as molecular mechanics and quantum mechanical methods used to characterize and identify relevant molecular properties and indicate some areas for future development of computational chemistry methods that could increase its effectiveness in the design of novel drugs.

Computer Simulation↗

PubMed1992

N-substituted pyrazino[2,3-c][1,2,6]thiadiazine 2,2-dioxides. A new class of diuretics.

The synthesis and evaluation of a new class of diuretic agents derived from the pyrazino[2,3-c][1,2,6]thiadiazine 2,2-dioxide ring system are described. Preliminary structure-activity relationships indicate that the nature and location of the substituents at different positions of the heterocycle are crucial for activity. Thus, a novel synthetic methodology has been developed to selectively introduce the desired substituents at different positions. From the study of the pharmacological properties (dose-response curves, duration of action, and acute toxicity) of the most active compounds, 4-amino-1,7-diethyl-6-methylpyrazino[2,3-c][1,2,6]thiadiazine++ + 2,2-dioxide (9) was selected for further investigation. Compound 9 (C10H15N5O2S) crystallizes in space group P21/a with unit cell dimensions a = 16.482 (1), b = 9.3484 (3), c = 8.333 (3) A, beta = 103.003 (3) degrees, Z = 4.

Animals↗

PubMed1991

Synthesis and biological screening of aminothiadiazine dioxides related to trimethoprim.

New derivatives of 3-amino-1,2,6-thiadiazine 1,1-dioxide have been synthesized and their antibacterial, antifungal and DHFR inhibitory activities evaluated. Their chemical structures have been established by means of analytical and NMR spectroscopic data. Among the compounds studied, the 4,4-dibromo derivative 11 showed fungistatic activity against C. albicans.

Animals↗

PubMed1990

Pectin Lyase Activity in a Penicillium italicum Strain.

An extracellular pectin lyase (PNL) [poly-(methoxygalacturonide)lyase; EC 4.2.2.10] produced by Penicillium italicum CECT 2294 grown on a surface bran (natural medium) or in a submerged (synthetic medium) culture was investigated. Both culture filtrates showed macerating activity at low pH on cucumber, potato, and orange tissues. The physicochemical properties of the enzyme obtained from both culture methods were identical, as well as its catalytic properties, which were assayed by different methods. The molecular mass of the PNL obtained by gel filtration chromatography was 22 kDa; the isoelectric point was 8.6, as determined by chromatofocusing; and the enzyme was able to catalyze the eliminative cleavage of pectins with low (37%) and high (from 54 to 82%) degrees of esterification. The PNL produced in liquid medium showed a K(m) for pectin (degree of esterification, 70%) of 3.2 mg/ml, and the optimum pH was 6.0 to 7.0. This enzyme was stable at 50 degrees C and at pH 8.0. The ability of this PNL to macerate plant tissues in acidic environmental conditions, its stability at low pH and temperatures up to 50 degrees C (thus preventing mesophilic microbial growth), and the absence of pectinesterase make this preparation useful for the food industry.

Journal Article↗

PubMedDate not supplied

Climbing a ladder: a step-by-step approach to understanding the concept of agroecosystem health.

Population and individual health is linked to agroecosystem health. To comprehend the concept of agroecosystem health, one should climb a ladder consisting of several successive steps, each rung presenting a certain degree of instability (conceptual difficulty and uncertainty) in an advisable but not inevitable order. Here we suggest a ladder consisting of the following concepts: ecosystem, agroecosystem, biodiversity, sustainability, ecosystem health, and agroecosystem health. Although these concepts are to a certain extent well understood and grasped by scientists, politicians, natural resource managers, and environmentalists, some steps are still highly debatable, unclear, and present a considerable degree of reluctance to be defined and understood. Consequently, much empirical and theoretical effort must be made to construct solid conceptual ladders made up of such steps. In this enterprise, a traditional reductionistic approach confining interpretations to narrow scientific disciplines is unadvisable. Holistic, transdisciplinary approaches are required to reach the desired goal.

Agriculture↗

PubMedDate not supplied

Phytoextraction and phytofiltration of arsenic.

Arsenic, a ubiquitous contaminant in groundwater and soils, is currently drawing much public attention. Arsenic-contaminated soils can be cleaned up via phytoextraction-the use of plants to extract the arsenic from soil and transport it into aboveground tissues. Arsenic removal from polluted soils can be carried out using hyperaccumulator ferns like the Chinese brake fern Pteris vittata, which accumulates very high concentrations of the element in aboveground tissues. The capacity of the plant to take up large concentrations of arsenic, even at low levels in soil, illustrates efficient bioaccumulation. The possibility of using Pteris ferns to remove arsenic from water by phytofiltration has been proposed.

Arsenic↗

PubMedDate not supplied

Bioluminescent bacterial biosensors for the assessment of metal toxicity and bioavailability in soils.

A major factor governing the toxicity of heavy metals in soils is their bioavailability. Traditionally, sequential extraction procedures using different extractants followed by chemical analysis have been used for determining the biologically available fraction of metals in soils. Yet, the transfer of results obtained on non-biological systems to biological ones is certainly questionable. Therefore, bioluminescence-based bacterial biosensors have been developed using genetically engineered microorganisms, constructed by fusing transcriptionally active components of metal resistance mechanisms to lux genes from naturally bioluminescent bacteria like Vibrio fischeri for the assessment of metal toxicity and bioavailability in polluted soils. As compared to chemical methods, bacterial biosensors present certain advantages, such as selectivity, sensitivity, simplicity, and low cost. Despite certain inherent limitations, bacterial bioluminescent systems have proven their usefulness in soils under laboratory and field conditions. Finally, green fluorescent protein-based bacterial biosensors are also applicable for determining with high sensitivity the bioavailability of heavy metals in soil samples.

Aliivibrio fischeri↗