An electrochemical aptasensor for Δ-tetrahydrocannabinol detection in saliva on a microfluidic platform.

We present a novel "on-off", cost-effective, rapid electrochemical aptasensor combined with a microfluidics cartridge system for the detection of Δ-THC (Δ-tetrahydrocannabinol) in human saliva via differential pulse voltammetry. The assay relied on the competitive binding between the Δ-THC and a soluble redox indicator methylene blue, using an aptamer selected via FRELEX. We found that the aptasensor can detected 1 nM of Δ-THC in PBS in a three-electrode cell system, while the sensitivity and both the dissociation constant (K) and association constant (K) were dependent on the aptamer density.

Molecular modeling in the design of peptidomimetics and peptide surrogates.

The most important natural sources of new leads are plant extracts, bacterial broths, animal venoms and peptides isolated from living organisms. However, only the three first have been used extensively in the development of new therapeutic agents. This is probably due to the low pharmacological profile exhibited by peptides, that requires a lengthy transformation to make them suitable as new leads.

Identification of selective inhibitors of acetylcholinesterase from a combinatorial library of 2,5-piperazinediones.

The potentiation of central cholinergic activity has been proposed as a therapeutic approach for improving cognitive function in patients with Alzheimer's disease. Increasing the acetylcholine concentration in brain by modulating acetylcholinesterase (AChE) activity is among the most promising strategies. We have used a combinatorial approach to identify different 2,5-piperazinediones (DKP) with AChE inhibitory activity.

Differential binding mode of diverse cyclooxygenase inhibitors.

Non-steroidal anti-inflammatory drugs (NSAIDs) are competitive inhibitors of cyclooxygenase (COX), the enzyme that mediates biosynthesis of prostaglandins and thromboxanes from arachidonic acid. There are at least two different isoforms of the enzyme known as COX-1 and -2. Site directed mutagenesis studies suggest that non-selective COX inhibitors of diverse chemical families exhibit differential binding modes to the two isozymes.

Toward the design of chemical libraries for mass screening biased against mutagenic compounds.

The ability to develop a chemical into a drug depends on multiple factors. Beyond potency and selectivity, ADME/PK and the toxicological profile of the compound play a significant role in its evaluation as a candidate for development. Those factors are being brought into bear earlier in the discovery process and even into the design of libraries for screening.

Synthesis and biological evaluation of 1,3,4-triaryl-3-pyrrolin-2-ones, a new class of selective cyclooxygenase-2 inhibitors.

The synthesis and structure activity relationships (SAR) of a series of novel selective COX-2 inhibitors are reported. The results show that some of the 1,3,4-triaryl-3-pyrrolin-2-ones 1 are more potent as COX-2 inhibitors than celecoxib, and that lactam Id has the same selectivity.

Modeling cyclooxygenase inhibition. Implication of active site hydration on the selectivity of ketoprofen analogues.

Molecular modeling studies performed on the two cyclooxygenase isozymes (COXs) suggest that active site hydration is crucial for understanding inhibitor selectivity. In this work, models have been constructed considering some implicit water molecules, placed in the position suggested by GRID, that participate in the dynamic hydrogen-bonding network at the polar active site entrance together with protein residues 355, 524, 120, and 513. The selectivity observed for ketoprofen (1) and the structural analogues 2 and 3 may be rationalized in terms of such implicit hydration.

Structural basis of the dynamic mechanism of ligand binding to cyclooxygenase.

Molecular modeling studies performed on the two cyclooxygenase (COX) isozymes suggest that the cavity at the mouth of the active site on the membrane domain that may act as an actual binding site of COX ligands. Actual docking of different inhibitors at this site provides a structural basis to explain the dynamics of COX inhibition.

Amygdalin binds to the CD4 receptor as suggested from molecular modeling studies.

The geometrical features of the proposed bioactive conformation of peptide T assessed by computational methods in a previous study, together with available structure-activity studies on peptide T, led us to propose a pharmacophore for the CD4-peptide T interaction. Subsequent, data base searching permitted us to identify amygdalin as a peptide T peptidomimetic.

New insights into the conformational requirements of B2 bradykinin antagonism.

The conformational profiles of a selected group of a new series of small linear and cyclic penta- and hexapeptides, inspired on the C-terminal segment of second-generation bradykinin (BK) antagonists, were independently computed in order to assess the chemical and geometrical requirements necessary for BK antagonism. Specifically, four cyclic peptides: cyclo-(Gly-Thi-D-Tic-Oic-Arg), cyclo-(Gly-Ala-D-Tic-Oic-Arg), cyclo-(Abu-Ala-Ser-D-Tic-Oic-Arg), cyclo-(Abu-D-Phe-Ala-D-Tic-Oic-Arg), and a linear peptide: Thi-Ser-D-Tic-Oic-Arg were selected for the present study. The first three BK analogs are capable to antagonize kinin-induced rabbit jugular vein and rabbit aorta smooth muscle contraction, while last two show no detectable affinity for the BK B2 receptor.