Molecular Topology and Other Promiscuity Determinants as Predictors of Therapeutic Class - A Theoretical Framework to Guide Drug Repositioning?

Much interest has been paid in the last decade on molecular predictors of promiscuity, including molecular weight, log P, molecular complexity, acidity constant and molecular topology, with correlations between promiscuity and those descriptors seemingly being context-dependent. It has been observed that certain therapeutic categories (e.g.

Computer-Aided Drug Design: An Overview.

The term drug design describes the search of novel compounds with biological activity, on a systematic basis. In its most common form, it involves modification of a known active scaffold or linking known active scaffolds, although de novo drug design (i.e.

Diabetes primary prevention program: New insights from data analysis of recruitment period.

Background: Primary Prevention of Diabetes Program in Buenos Aires Province evaluates the effectiveness of adopting healthy lifestyle to prevent type 2 diabetes (T2D) in people at high risk of developing it. We aimed to present preliminary data analysis of FINDRISC and laboratory measurements taken during recruitment of people for the Primary Prevention of Diabetes Program in Buenos Aires Province in the cities of La Plata, Berisso, and Ensenada, Argentina.

Methods: People were recruited through population approach (house-to-house survey by FINDRISC in randomized areas) and opportunistic approach (FINDRISC completed by participants during consultations for nonrelated prediabetes/diabetes symptoms in public and private primary care centres of cities involved).

TfVPS32 Regulates Cell Division in the Parasite Tritrichomonas foetus.

The flagellated protist Tritrichomonas foetus is a parasite that causes bovine trichomonosis, a major sexually transmitted disease in cattle. Cell division has been described as a key player in controlling cell survival in other cells, including parasites but there is no information on the regulation of this process in T. foetus.

ACE-inhibitory peptides from bovine caseins released with peptidases from Maclura pomifera latex.

In work reported here, a proteolytic extract prepared from Maclura pomifera latex was employed to hydrolyze bovine caseins. Densitograms of Tricine-sodium-dodecyl-sulfate-polyacrylamide-gel electrophoresis (SDS-PAGE) indicated that the caseins were considerably degraded after a 10-min reaction. The degree of hydrolysis determined by the 2,4,6-trinitrobenzenesulfonic-acid method was 17.

Neurons of the rat cervical spinal cord express vimentin and neurofilament after intraparenchymal injection of kainic acid.

Intermediate filaments (IF) can be altered under disorders such as neurodegenerative diseases. Kainic acid (KA) induce behavioral changes and histopathological alterations of the spinal cord of injected rats. Our goal was to evaluate the IF expression in neurons during this injury model.

Long-lasting training in the Barnes maze prompts hippocampal spinogenesis and habituation in rats.

There is a constant need to assess spatial memory in small rodents to elucidate the basics of cognition in neuroscience experiments. Thus, the significance of the Barnes maze in the biology of hippocampal and cortical neural function cannot be overemphasized. Despite the wide use of the Barnes maze, the effect of maze task training on the structure of hippocampal neurons is yet to be elucidated.

Assessment of Cu-Zn EDTA Parenteral Toxicity in Calves.

Copper (Cu) parenteral administration is used in a beef cow-calf operations to prevent or correct Cu deficiency in bovines. At present, Zinc (Zn) salts have been incorporated to complement Cu antioxidant effect. A risk of hepatotoxicity generated by overdose is a negative consequence of injectable Cu application.

Current State and Future Perspectives in QSAR Models to Predict Blood- Brain Barrier Penetration in Central Nervous System Drug R&D.

The Blood-Brain Barrier (BBB) is a physical and biochemical barrier that restricts the entry of certain drugs to the Central Nervous System (CNS), while allowing the passage of others. The ability to predict the permeability of a given molecule through the BBB is a key aspect in CNS drug discovery and development, since neurotherapeutic agents with molecular targets in the CNS should be able to cross the BBB, whereas peripherally acting agents should not, to minimize the risk of CNS adverse effects. In this review we examine and discuss QSAR approaches and current availability of experimental data for the construction of BBB permeability predictive models, focusing on the modeling of the biorelevant parameter unbound partitioning coefficient (Kp,uu).

Multibiomarker response in ten spotted live-bearer fish Cnesterodon decemmaculatus (Jenyns, 1842) exposed to Reconquista river water.

The aim of this paper is to assess the water quality to chemical pollution at Roggero Dam, the headwater of the Reconquista river, and to perform a Cadmium (Cd) contamination pulse simulation through a wide battery of biomarkers which included: genotoxicity and enzymatic biomarker parameters on a neotropical teleost fish namely Cnesterodon decemmaculatus. Water samples were taken in order to determine the river's physicochemical profile. An integrative approach was applied using a biomarker index.

Characterization of paneth cells in alpacas (Vicugna pacos, Mammalia, Camelidae).

Paneth cells are secretory epithelial cells of the innate immune system of the intestine of several mammals, including alpacas. Little is known about the latter; thus, in the present study we described the morphology and histochemical characteristics of Paneth cells in healthy fetuses, and young and adult alpacas. For this purpose, samples of duodenum, jejunum and ileum were taken from 6 fetuses at different days of pregnancy (between days 221-330), 66 offsprings (between 0 and 45-days-old) and 5 adult alpacas (>2-years-old).

Novel cruzipain inhibitors for the chemotherapy of chronic Chagas disease.

Despite current efforts worldwide to develop new medications against Chagas disease, only two drugs are available, nifurtimox and benznidazole. Both drugs require prolonged treatment and have multiple side effects and limited efficacy on adult patients chronically infected with Trypanosoma cruzi. Recently, computer-guided drug repositioning led to the discovery of the trypanocidal effects of clofazimine and benidipine.

Neuroendocrine Regulation of Metabolism.

Given the current environment in most developed countries, it is a challenge to maintain a good balance between calories consumed and calories burned, although maintenance of metabolic balance is key to good health. Therefore, understanding how metabolic regulation is achieved and how the dysregulation of metabolism affects health is an area of intense research. Most studies focus on the hypothalamus, which is a brain area that acts as a key regulator of metabolism.

High Risk of Metabolic and Adipose Tissue Dysfunctions in Adult Male Progeny, Due to Prenatal and Adulthood Malnutrition Induced by Fructose Rich Diet.

The aim of this work was to determine the effect of a fructose rich diet (FRD) consumed by the pregnant mother on the endocrine-metabolic and in vivo and in vitro adipose tissue (AT) functions of the male offspring in adulthood. At 60 days of age, rats born to FRD-fed mothers (F) showed impaired glucose tolerance after glucose overload and high circulating levels of leptin (LEP). Despite the diminished mass of retroperitoneal AT, this tissue was characterized by enhanced LEP gene expression, and hypertrophic adipocytes secreting in vitro larger amounts of LEP.

Discovery of novel polyamine analogs with anti-protozoal activity by computer guided drug repositioning.

Chagas disease is a parasitic infection caused by the protozoa Trypanosoma cruzi that affects about 6 million people in Latin America. Despite its sanitary importance, there are currently only two drugs available for treatment: benznidazole and nifurtimox, both exhibiting serious adverse effects and limited efficacy in the chronic stage of the disease. Polyamines are ubiquitous to all living organisms where they participate in multiple basic functions such as biosynthesis of nucleic acids and proteins, proliferation and cell differentiation.

Haematologic alterations caused by Ipomoea carnea in experimental poisoning of guinea pig.

Ipomoea carnea subsp. fistulosa (Convolvulaceae) causes poisoning of goats, sheep and cattle in many tropical and subtropical countries. The pathophysiology of this poisoning mainly involves an abnormal glycoprotein metabolism.

Functional and histopathological changes induced by intraparenchymal injection of kainic acid in the rat cervical spinal cord.

Kainic acid (KA) is an analog of the neurotransmitter glutamate and is widely used as an excitotoxic agent to lesion spinal cord networks, thus, providing an interesting model to learn basic mechanisms of spinal cord injury. The present work was aimed to evaluate motor and sensory performance of rats and analyze morphometric parameters of spinal cord neurons after KA injection. Animals were injected either with 0.

High-throughput drug repositioning for the discovery of new treatments for Chagas disease.

Despite affecting around 8 million people worldwide and representing an economic burden above $7 billion/ year, currently approved medications to treat Chagas disease are still limited to two drugs, nifurtimox and benznidazole, which were developed more than 40 years ago and present important efficacy and safety limitations. Drug repositioning (i.e.

Computer-guided drug repurposing: identification of trypanocidal activity of clofazimine, benidipine and saquinavir.

In spite of remarkable advances in the knowledge on Trypanosoma cruzi biology, no medications to treat Chagas disease have been approved in the last 40 years and almost 8 million people remain infected. Since the public sector and non-profit organizations play a significant role in the research efforts on Chagas disease, it is important to implement research strategies that promote translation of basic research into the clinical practice. Recent international public-private initiatives address the potential of drug repositioning (i.

Mathematical modelling of fluid transport and its regulation at multiple scales.

Living matter equals water, to a first approximation, and water transport across barriers such as membranes and epithelia is vital. Water serves two competing functions. On the one hand, it is the fundamental solvent enabling random mobility of solutes and therefore biochemical reactions and intracellular signal propagation.

Between physics and metaphysics: structure as a boundary concept.

The notion of structure is found to be used in a great number of theories, scientific research programs and world views. However, its uses and definitions are as diverse as the objects of the scientific disciplines where it can be found. Without trying to recreate the structuralist aspiration from the mid XX century, which believed to have found in this notion a common transdisciplinary language, I discuss a specific aspect of this concept that could be considered a constant in different perspectives.

Applications of nanosystems to anticancer drug therapy (Part II. Dendrimers, micelles, lipid-based nanosystems).

The great efforts of many researchers have brought down some of the barriers that exist to turn a good in vitro compound into a potential in vivo drug. The advent of pharmaceutical nanotechnology has allowed an arsenal of drugs with poor stability, low solubility, high off-target toxicity and other disadvantageous features, to be accessible as pharmaceutical products that could be administered to a patient. Nanotechnology was introduced in drug delivery very long ago, but has flourished with unprecedented intensity during the last twenty years and now a diversity of nano-based preparations are at clinical stage of development or already available in the market.

Applications of nanosystems to anticancer drug therapy (Part I. Nanogels, nanospheres, nanocapsules).

One of the greatest challenges in cancer drug therapy is to maximize the effectiveness of the active agent while reducing its systemic adverse effects. To add more, many widely-used chemoterapeutic agents present unfavorable physicochemical properties (e.g.

An integrated drug development approach applying topological descriptors.

We describe the opportunities posed by computer-assisted drug design in the light of two aspects of the current drug discovery scenario: the decline of innovation due to high attrition rates at clinical stage of development and the combinatorial explosion emerging from exponential growth of feasible small molecules and genome and proteome exploration. We present an overview of recent reports from our group in the field of rational drug development, by using topological descriptors (either alone, or in combination with different 3D approaches) and a diversity of modeling techniques such as Linear Discriminant Analysis and the Replacement Method. Modeling efforts aimed at the integrated prediction of several significant molecular properties in the field of drug discovery, such as pharmacological activity, aqueous solubility, human intestinal permeability and affinity to P-glycoprotein (ABCB1, MDR1) are reviewed.