Development of a novel pharmacophore model to screen specific inhibitors for the serine-threonine protein phosphatase calcineurin.

Calcineurin (CaN) is a calcium/calmodulin-dependent serine/threonine phosphatase with a crucial role in cellular homeostasis. It is also the target of the Food and Drug Administration (FDA) approved immunosuppressant drugs FK506 and cyclosporine A. Recent work from our group and others indicated that an uncontrolled increase in CaN activity causes synaptic dysfunction and neuronal death in various models of neurodegenerative diseases associated with calcium dysregulation.

A Strategic Program for Risk Assessment and Intervention to Mitigate Environmental Stressor-Related Adverse Pregnancy Outcomes in the Indian Population.

Global environmental stressors of human health include, but are not limited to, conflict, migration, war, natural disasters, climate change, pollution, trauma, and pandemics. In combination with other factors, these stressors influence physical and mental as well as reproductive health. Maternal stress is a known factor for adverse pregnancy outcomes such as preterm birth (PTB); however, environmental stressors are less well-understood in this context and the problem is relatively under-researched.

Projected Wine Grape Cultivar Shifts Due to Climate Change in New Zealand.

Climate change has already been affecting the regional suitability of grapevines with significant advances in phenology being observed globally in the last few decades. This has significant implications for New Zealand, where the wine industry represents a major share of the horticultural industry revenue. We modeled key crop phenological stages to better understand temporal and spatial shifts in three important regions of New Zealand (Marlborough, Hawke's Bay, Central Otago) for three dominant cultivars (Merlot, Pinot noir, and Sauvignon blanc) and one potential new and later ripening cultivar (Grenache).

Understanding spatial and temporal variability of N leaching reduction by winter cover crops under climate change.

Winter cover crops are sown in between main spring crops (e.g. cash and forage crops) to provide a range of benefits, including the reduction of nitrogen (N) leaching losses to groundwater.

Projecting the effect of climate change on residential property damages caused by extreme weather events.

New Zealand's public insurer for natural hazards, the Earthquake Commission (EQC), provides residential insurance for some weather-related damage. Climate change and the expected increase in intensity and frequency of extreme weather-related events are likely to translate into higher damages and thus an additional financial liability for the EQC. We project future insured damages from extreme precipitation events associated with future projected climatic change.

Synthesis and application of β-carbolines as novel multi-functional anti-Alzheimer's disease agents.

The design, synthesis and assessment of β-carboline core-based compounds as potential multifunctional agents against several processes that are believed to play a significant role in Alzheimer's disease (AD) pathology, are described. The activity of the compounds was determined in Aβ self-assembly (fibril and oligomer formation) and cholinesterase (AChE, BuChE) activity inhibition, and their antioxidant properties were also assessed. To obtain insight into the mode of action of the compounds, HR-MS studies were carried out on the inhibitor-Aβ complex formation and molecular docking was performed on inhibitor-BuChE interactions.

Sulfonamides as multifunctional agents for Alzheimer's disease.

Sulfonamide linker-based inhibitors with extended linear structure were designed and synthesized with the aim of producing multifunctional agents against several processes involved in the pathology of Alzheimer's disease (AD). The potency of the compounds were assessed in the inhibition of Aβ self-assembly (fibril and oligomer formation), in modulating cholinesterase (AChE, BuChE) activity, and scavenging free radicals. Several compounds exhibited promising Aβ self-assembly and cholinesterase inhibition and in parallel, showed good free radical scavenging properties.

Design, synthesis and biological activity of multifunctional α,β-unsaturated carbonyl scaffolds for Alzheimer's disease.

A series of compounds containing an α,β-unsaturated carbonyl moiety, such as chalcones and coumarins were designed, synthesized and tested in a variety of assays to assess their potential as anti-Alzheimer's disease (AD) agents. The investigations included the inhibition of cholinesterases (AChE, BuChE), the inhibition of amyloid beta (Aβ) self-assembly and the disassembly of preformed Aβ oligomers. Several compounds showed excellent potential as multifunctional compounds for AD.

Diaryl hydrazones as multifunctional inhibitors of amyloid self-assembly.

The design and application of an effective, new class of multifunctional small molecule inhibitors of amyloid self-assembly are described. Several compounds based on the diaryl hydrazone scaffold were designed. Forty-four substituted derivatives of this core structure were synthesized using a variety of benzaldehydes and phenylhydrazines and characterized.

Introduction to spin label electron paramagnetic resonance spectroscopy of proteins.

An undergraduate laboratory exercise is described to demonstrate the biochemical applications of electron paramagnetic resonance (EPR) spectroscopy. The β93 cysteine residue of hemoglobin is labeled by the covalent binding of 3-maleimido-proxyl (5-MSL) and 2,2,5,5-tetramethyl-1-oxyl-3-methyl methanethiosulfonate (MTSL), respectively. The excess spin label is removed by gel-exclusion chromatography.

Pharmacophore Modeling, virtual and in vitro screening for acetylcholinesterase inhibitors and their effects on amyloid-β self- assembly.

One of the most promising methods of unveiling the pharmacology of marketed drugs is to screen them against new biological targets. In an attempt to find inhibitors for acetylcholinesterase (AChE), the Drug Bank Database and natural alkaloids with other known medicinal values were screened through a four-point pharmacophore built in this study. The development of the pharmacophore was based on a structurally diverse set of reported AChE inhibitors and was validated using a separate set of known inhibitors.

Structure-activity relationships of organofluorine inhibitors of β-amyloid self-assembly.

A broad group of structurally diverse small organofluorine compounds were synthesized and evaluated as inhibitors of β-amyloid (Aβ) self-assembly. The main goal was to generate a diverse library of compounds with the same functional group and to observe general structural features that characterize inhibitors of Aβ oligomer and fibril formation, ultimately identifying structures for further focused inhibitor design. The common structural motifs in these compounds are CF(3) -C-OH and CF(3) -C-NH groups that were proposed to be binding units in our previous studies.

Disassembly of preformed amyloid beta fibrils by small organofluorine molecules.

A potential therapeutic approach for Alzheimer's disease is to reduce the amount of toxic amyloid-beta oligomers and fibrillar amyloid plaques. In order to contribute to this approach the ability of small organofluorine compounds that were previously reported as successful inhibitors of fibrillogenesis to destabilize preformed fibrils of the amyloid-beta peptide was studied. These organofluorine molecules including chiral compounds were tested in vitro using standard methods based on Thioflavin-T (THT) fluorescence spectroscopy, atomic force microscopy (AFM) and Fourier-transform infrared spectroscopy (FTIR).

Heteropoly acid-catalyzed microwave-assisted three-component aza-Diels-Alder cyclizations: diastereoselective synthesis of potential drug candidates for Alzheimer's disease.

A highly diastereoselective microwave-assisted three component synthesis of azabicyclo[2.2.2]octan-5-ones by a silicotungstic acid-catalyzed aza-Diels-Alder cyclization is described.

Effect of chirality of small molecule organofluorine inhibitors of amyloid self-assembly on inhibitor potency.

The effect of enantiomeric trifluoromethyl-indolyl-acetic acid ethyl esters on the fibrillogenesis of Alzheimer's amyloid beta (Abeta) peptide is described. These compounds have been previously identified as effective inhibitors of the Abeta self-assembly in their racemic form. Thioflavin-T Fluorescence Spectroscopy and Atomic Force Microscopy were applied to assess the potency of the chiral target compounds.