Dr. Tara Sirvent
Professor of Biochemistry

Affect of metal accumulation in the medicinal plant Hypericum perforatum

We are investigating a plant that is known as St. John’s wort. This plant has been used for over three centuries for treating skin and mood disorders. We know that one family of compounds called the hypericins is responsible for the anti-viral and anti-microbial action of the plant. These compounds (which are a member of the polyketide super-family) are synthesized via a pathway similar to fatty acids. We have received funding from the National Science Foundation to study hypericin biosynthesis. In addition, we are intrigued by the fact that H. perforatum accumulates heavy metals. We are, therefore, trying to dissect the relationship between heavy metal accumulation and hypericin production using HPLC and ICP techniques.

(1 student)

Dr. SiauMin Fung
Assistant Professor of Molecular Genetics

SiauMin Fung
Brain development is an orderly process, but the fundamental steps at its earliest stages remain unclear. Drosophila is an ideal model to characterize these critical maturational mechanisms because they possess neuroblasts that generate neurons and glia throughout the developing brain. These neuroblasts are capable making new cells through a process known as the asymmetrical cell division. In each division, neuroblasts creating one cell that continues to be a neuroblast (maintaining/renewing themselves) and the other cells, the ganglion mother cells will differentiation into neurons and glia (differentiation). Although many proteins and pathways may regulate neuroblasts fate, our preliminary results suggest that E-cadherin (Shg) plays a central role.Our findings from Summer Research 2013:

1)    Number of neuroblasts decreased as Drosophila developed from larval to the pupa stage. The number of GMCs is maintained throughout the pupal stages. (Elizabeth Swezey).

2)    Shg expression switches from dividing cells to express in glial cells at 72 hrs APF (Michael Lum)

3)    Over expressed E-cadherin during pupal development displayed a greater occurrence of Brdu stained cells (Alexis Reyes)

Therefore, the overarching goal of the current proposal is to characterize the molecular mechanisms of E-cadherin during neuronal cell differentiation in relation to hormonal changes as Drosophila developed through the pupal stages
Ecdysone affects brain development during Drosophila pupal development

Ecdysone is a major steroid hormone in insect. It plays essential roles in coordinating metamorphosis. This project will focus on the role of ecdysone in regulating brain development of Drosophila from larval to the pupal stage. Experiments will include characterizing the changes occur throughout development of the engrailed positive neuronal lineage. The effects of misexpression and absence of ecdysone to this lineage will be examined.

(1 student)

 
Characterizing the Role of E-chadherin in Neuroblast and Ganglion Mother cells number 

During the larval stage, E-cadherin has shown to promote neuroblast proliferation. In this project, we will use Drosophila genetics to create mutant E-cadherin cells to elucidate the role of E- cadherin in neuroblast proliferation, in the pupal stage. As removing E-cadherin results in a lethal mutant, we will attempt to mis-express dominant negative mutant of  E-cadherin at a specific stage of development.  This experiment will determine the role of E-cadherin in neuroblast and ganglion mother cell numbers during pupal stages. 

(1 student)

 

Dr. Lorance
Professor of Chemistry

Hydrothermal Reductions Promoted by Common Metals 

It has been observed that low-oxidation state minerals under hydrothermal conditions (≥200 °C in water under sufficient pressure to maintain a liquid state) can reduce organic compounds.  These reactions have a high potential for development as “green chemistry” processes, esp. if cheap and non-toxic or low-toxicity metals can be found for use as agents.  A prime system for consideration is the reduction of organic compounds by iron, as scrap iron would be a cheap, abundant, and environmentally friendly source of reducing agent.  Toward this end, the following reactions will be investigated at temperatures at and above 200°C: 

To achieve these elevated temperatures, the reactions are sealed in heavy-walled borosilicate tubing (placed in black pipe shields for safety) and heated in an oven for variable lengths of time.  When the reaction period is over, the tubes are quenched in cold water, cut open, and the contents extracted with DCM and analyzed by GC/MS and GC/FID.

(1-2 students)

iCAP 6200 ICP OES

iCAP 6200 ICP OES

Cuprous Ion Oxidation under Hydrothermal Conditions

In the course of other hydrothermal investigations, it was observed that Cu(II) could be used to oxidize alcohols to aldehydes and carboxylic acids in a fashion that allows the end product of the oxidation to be selected.  Copper(II) is not a commonly known oxidant for organic hydroxyl groups and has, to our knowledge, never been employed in an aqueous medium. 

To investigate the scope and potential of this green, selective oxidation, we intend to oxidize various alcohols at temperatures at or above 100°C.  At 100°C, the reaction can be monitored by taking aliquots from a refluxing system.  Above 100°C, the reactions are sealed in heavy-walled borosilicate tubing (placed in black pipe shields for safety) and heated in an oven for variable lengths of time.  When the reaction period is over, the tubes are quenched in cold water, cut open, and the contents extracted with DCM and analyzed by GC/MS and GC/FID.

(1 student)

iCAP 6200 ICP OES

iCAP 6200 ICP OES

Dr. John Terhorst
Adjunct Professor of Biochemistry

My research projects use computers to explore questions in modern chemistry that experimental methods often cannot answer.  Specifically, we apply chemical theory, statistics, and informatics to study the relationship between the structure of organic molecules and their activity in biological systems. This “quantitative structure-activity relationship,” or QSAR, allows us to design molecules with certain desired pharmacological properties, with the ultimate goal of developing therapeutic agents targeting infectious, inflammatory, and hyperproliferative diseases.

Dr. John Terhorst

Expanding and Testing a Fragment Library for Pharmaceutical Design

The foundation of any QSAR analysis begins with the fragment library: a database of molecular fragments and their associated geometric, physical, and chemical properties. At VU/SURP in 2013, we populated and tested a new library for discovery of inhibitors of HIV-1 reverse transcriptase, a key enzyme in the retroviral reproductive pathway. An initial screening revealed 16 drug candidates that met or exceeded expected values predicted for drug-likeness, including log P, solvent-accessible surface area, Caco-2 and MDCK cell permeability, and hydrogen bonding. Of the 16 candidates, six exhibited moderate predicted binding affinities (6-7 kcal/mol) to the allosteric site of HIV-RT.  Our most promising candidates feature three imidazole cores coupled by methylene and amino linkers. As an undergraduate researcher on this project and with the assistance of Dr. Terhorst, your job will be to continue to expand and test this library in order to design and optimize new and existing drug candidates.

(1 student)

HIV-1 Reverse Transcriptase

HIV-1 Reverse Transcriptase

Exploring Dihedral Torsion Profiles with Implicit Solvent Models

Molecular mechanics are central to applications in computer-aided drug design. Of particular interest is the ensemble of conformations defined by one or more dihedral torsions within a given molecule. Often it is the case that these torsions give rise to unique molecular shapes, which can affect a potential drug’s ability to bind (or not bind) to its intended target. This project involves examining the dihedral torsion profiles of drug-like organic molecules in an aqueous environment to evaluate, among other things, the effects of solvation and substitution on molecular shapes. As an undergraduate researcher on this project and with the assistance of Dr. Terhorst, your job will be to use chemical simulations to characterize the torsional energies of derivatives of benzene, pyridine, pyrimidine, pyran, furan, thiophene, and other heterocycles, with and without the effects of solvation by water; comparing the two sets can give insight into how the different classes of molecules conform under biological conditions and what energies are involved in their conformational equilibria.

(1 student)

DNA in a PCM Solvent Cavity

DNA in a PCM Solvent Cavity

Understanding Resonance Energies using Isodesmic Reactions

For students with an interest in exploring more fundamental concepts in physical organic chemistry, this project offers an opportunity to study the energetic impact of resonance and aromaticity on a wide range of conjugated ring systems.  We will exploit simulations of homoisodesmic reactions to calculate resonance energies on ring systems for cyclobutadiene and higher. A variety of semi-empirical methods (AM1, PM3, PDDG/PM3, etc.) will be used for each reaction, allowing us to understand the strengths and weaknesses of different methods and illustrating the importance of choosing the appropriate tool to suit the task at hand. Results are to be compared with available experimental and theoretical data in the primary literature.

(1 student)

The Structure of a Liquid: How Solutes Affect Solvents (and Vice Versa)

An overarching goal in molecular design is to understand how a molecule will behave in any given environment. For instance, the interior of a protein or enzyme is significantly more hydrophobic than its outer surface, and so the environment that a potential ligand will experience changes throughout the process of binding with its host. To explore this phenomenon, we will select a number of solvents of interest and conduct Monte Carlo simulations to determine each liquid’s heat capacity, density, and heat of vaporization. The chosen solvents should exhibit a variety of properties, ranging from very nonpolar to very polar and possessing different hydrogen bonding/accepting patterns. Several solutes of interest will also be sampled in Monte Carlo procedures in the gas phase and in each of the chosen solvents. Physical properties determined from the different simulations will be compared to one another to understand the impact of solvation on the structure of each solute and to explore the impact of the solute on the structure and properties of each liquid. Properties of pure liquids can be compared to experimental and theoretical results in the literature.

(1 student)