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The 3d animation facility has covered topics that span from Gleevec's mechanism of action, to the factors effecting drug distribution in the body. It has become a collaborative effort between faculty and students to produce educational tools to facilitate the explanation of complex topics to their peers. Click on the links to the left to access all of our animations and learn more about our program and facilities at the URI college of Pharmacy.

Cisplatin

Cisplatin is in a class of drugs known as platinum containing compounds used to treat various types of cancers including metastatic testicular and ovarian tumors. The molecule was first discovered in 1845, but did not receive FDA approval until 1978. Today it is known as the "penicillin of cancer drugs," because it is so effective for many different cancers. There are three key players involved in Cisplatin's mechanism: (1) Cisplatin, (2) DNA (3) and an HMG Protein. Most Cisplatin enters the body through active transport, but some molecules are passively defused through the cell membrane.

Once in the nucleus, Cisplatin can form an adduct with two consecutive guanine bases within a strand of DNA. The molecule loses its chlorine atoms in exchange for the nitrogen atoms of the target guanines. Cisplatin can bond more tightly with nitrogen because nitrogen balances the platinum charge more effectively than chlorine.

It is this adduct-induced DNA bend that allows binding of proteins which contain the high mobility group, HMG domain. Once the protein is bound to the DNA, it inserts a wedge-like phenyl group of phenylalanine 37 into the widened minor groove created by the bend. The tightly bound HMG protein causes destacking of the nucleotide bases, resulting in the DNA helix becoming kinked. In this way, Cisplatin can be thought of as a monkey wrench in the DNA repair system. With the HMG protein bound to the DNA, the modified strand is not repaired properly and so the cell dies. The success of Cisplatin depends on its ratio of efficacy between cancerous and healthy cells.

 

Created by:

Nick O'Brien
STA Program

 

 

 

 

 

Dr. Bongsup Cho
Professor of Biomedical and Pharmaceutical Sciences
College of Pharmacy




DNA Adduct Conformation

Arylamines belong to an important class of environmental carcinogens which are implicated in the etiology of many human cancers. 2-Aminofluorene and its derivatives are prototype arylamine carcinogens that form two DNA adducts in vivo: AF and AAF. AF is the major and most persistent adduct. It is known to exist in a sequence-dependent equilibrium between external B-type and stacked S-conformers, as defined by the location (major groove and base-displaced, respectively) of the carcinogen moiety. A minor groove binding wedged (W)-conformer has also been observed in duplexes in which the lesion is mismatched with purine bases. The dynamics of the AF-induced B/S/W-heterogeneity have been shown to be modulated by both the base sequence contexts and the progression for the length of primers, and contribute to polymerase activity through a long-range effect. The sequence effects on adduct conformation and the nature of the polymerase are key factors for determining the mutational outcomes of these important carcinogens. This animation shows the rotating views of the external B-type (B), base-displaced stacked (S), minor groove wedge (W)-conformers. The modified dG and the complementary dC are shown in cyan and green CPK, respectively, and the aminofluorene carcinogen moiety is highlighted with red CPK.

Created by:

Nick O'Brien
STA Program

 

 

 

Dr. Bongsup Cho
Professor of Biomedical and Pharmaceutical Sciences
College of Pharmacy




HDAC Inhibitor, A New Anticancer Drug

Zolinza is a new kind of anticancer drug based on heritable epigenetic modification of gene function. Epigenetic processes modulate when genes are expressed or repressed, without changes in the DNA sequence. Histones are proteins that play a role in the regulation of transcription by helping to condense the genetic material DNA into its compact form. Histones play a major role in helping transcription factors to bind to specific area of the DNA.

Modification of histone proteins can control the tightness of the DNA around the histone proteins and consequently control the expression of the genes. An enzyme called Histone Deacetylase (HDAC) performs deacetylation. HDAC interacts with the acetylated lysine on the surface of histone, causing the removal of acetyl from the structure. When the deacetylation occurs, the histone surface becomes positive and the result is an increase in the strength of a histone's grasp on a DNA segment. As each acetyl is removed, the histone grasps becomes increasingly stronger.

So long as normal levels of HDAC are present, there isn't a problem. However, when abnormally high levels of HDAC exist as in cancer cells, deacetylation becomes out of control. An over-expressed HDAC causes too much deacetylation to a histone, which in turn grasps too tightly to the DNA. The result of this that the segment of DNA associated to the over deacetylated histone becomes squeezed so tight it becomes silenced. In other words, the DNA is no longer readable.

This creates a problem when the piece of DNA that is silenced is vital to maintain the cell cycle. One such example is p53, a tumor suppressor gene. Excessive deacetylation causes the associated histone to silence the tumor suppressing DNA segment, resulting in uncontrollable cell growth, i.e, cancer cells. The solution to this problem is design HDAC inhibitors, which block out HDAC. When a drug such as Zolinza docks into the active site of the enzyme, further deacetylation is prevented and the histone does not increase it's grip on the DNA segment. Consequently, the DNA segment remains accessible for transcription, and the cells can continue working with the DNA segment as it naturally would.

 

Created by:

Neight Haskins
STA Program

New Media Production

Class 2007

 

 

Dr. Bongsup Cho
Professor of Biomedical and Pharmaceutical Sciences
College of Pharmacy




Gleevec's Mechanism of Action

The animation begins by introducing the Philadelphia Chromosome, the result of a reciprocal translocation between chromosomes 9 and 22.  More specifically the breakpoint cluster region (BCR) of chromosome 22 is fused with part of the Abelson (ABL) gene on chromosome 9.  The resulting BCR-ABL genetic domain now located within chromosome 22 and codes for a mutant tyrosine kinase also known as BCR-ABL.  Under normal circumstances tyrosine kinase proteins respond to external cellular messaging proteins, and ultimately initiate a series of reactions that culminate in cellular replication.  Conversely, BCR-ABL is constitutively active, meaning it does not require activation by the aforementioned cellular messaging proteins in order to stimulate cellular replication.  This results in acceleration of cell division, an inhibition of DNA repair, overall genomic instability, and the fatal blast crisis characteristic of chronic myelogenous leukemia. 

            The animation progresses to introduce Gleevec (imatinib), the first in a class of drugs that specifically target and competively inhibit the ATP binding site on BCR-ABL tyrosine kinase.  This prevents the ABL domain from phosphorylating the tyrosine residue, and as a result preventing the proliferation of hematopoietic cells that express BCR-ABL.  Therapy with imatinib results in a dramatic reduction of tumor clone cells and the occurrence of blast crisis’, through targeted drug treatment which leaves health cells unscathed. 

 

Created by:

Nelson Caetano
Class of 2007
Pharmacy

 

 

Dr. Bongsup Cho
Professor of Biomedical and Pharmaceutical Sciences
College of Pharmacy




Factors Affecting Drug Distribution

This animation presents 4 major factors that effect a drugs distribution in the body: Organs of high perfusion, protein binding, molecular size, and polarity. This animation is 1 of the 4 utilized in a study evaluating educational innovations at Brown University.

 

Created by:

Nelson Caetano
Class of 2007
Pharmacy

 

 

Dr. Jef Bratberg

Clinical Assistant Professor of Pharmacy Practice

College of Pharmacy



G Protein Receptor (Take II)

This animation describes what takes place with a G protein receptor. G Protein Coupled Receptors (GPCRs) are proteins embedded in the surface of cells. GPCRs comprise the largest superfamily of proteins in the body. More than 1,000 different GPCRs have been identified since the first receptors were cloned. These proteins receive chemical signals from outside the cell and pass the signal into the cell, so that the cell can respond to the signal. The structures of the endogenous ligands for GPCRs are exceptionally diverse. They include biogenic amines such as norephnephrine and serotonine, peptides, glycoproteins, lipids, nucleotides, ions, and proteases. The sensation of exogenous stimuli, such as light, odors, and taste, is also mediated by this class of receptors. Activation of the receptor causes an effector inside the cell to produce a second signal chemical, which eventually triggers the cell to react to the original external chemical signal.

A ligand, in this case Norepinepherine (NE), binds to the receptor and induces a conformational change. This conformational change activates the a/b complex. The complex is bound to GDP while it is inactive. GTP replaces GDP, thus activating the Alpha subunit. The activated Alpha subunit undergoes a conformational change and activates Adenylate Cyclase. Once the Adenylate Cyclase is activated, it is then able to convert ATP. The products of ATP conversion are c-AMP and two phosphate molecules. c-AMP is a second messenger used in many processes required for cell survival and growth.

 

Created by:

Nelson Caetano
Class of 2007
Pharmacy

 

 

Dr. Jef Bratberg

Clinical Assistant Professor of Pharmacy Practice

College of Pharmacy



Nucleotide Excision Repair (NER) of Carcinogen Adducts

This cartoon animation shows how DNA damage is fixed by a process called “nucleotide excision repair” (NER). The target is the DNA adducted by the human bladder carcinogen 4-aminobiphenyl. The NER machinery represented by cartoon mice takes the problematic portion of the DNA out and trash it. The missing strand is replaced by a new DNA strand.

Created by:

Joshua Vallee
College of Pharmacy
Class of 2007

 

 


Dr. Bongsup Cho
Professor of Biomedical and Pharmaceutical Sciences
College of Pharmacy



DNA Damage and Protection

The genetic material DNA is under constant attack from the environment.  There are two parts in this animation.  The first half of the animation illustrates how DNA is damaged by reactive free radical and is protected by SOD/CAT.   The second half shows methylation by the endogeneous cofactor S-adenosyl methionine (SAM).  The methylation damage is reversed by action of by alkytransferase such as AGT.  All the enzymes involved are represented by cute mice.

Created by:

Keith Mathieu
Class of 2007
Pharmacy

 

 

Dr. Bongsup Cho
Professor of Biomedical and Pharmaceutical Sciences
College of Pharmacy



Bleomycin

Bleomycin is a popular DNA-reactive anticancer agent. This animation consists of three parts, 1) the first is a simple backdrop that shows DNA and the drug in the nucleus environment focusing on the areas of interest, allowing the instructor time to go over some basics such as structure characteristics of DNA and Bleomycin. 2) the second consists of Bleomycin intercalating into DNA, the bisthiazole tail inserts into the helix area and then is positioned to produce free hydroxyl radicals. 3) the final segment shows how the drug in the presence of ferric ion and oxygen undergoes a dynamic action to form extremely reactive hydroxyl radical in situ and degrade the sugar structure of DNA. This action results in loss of genetic information necessary for DNA replication in cancer cells (and some normal cells!).


 

 

 

Created by:

Kevin McConeghy
Student Technology Assistant
Pharmacy Class of 2010

 

 

Dr. Bongsup Cho
Professor of Biomedical and Pharmaceutical Sciences
College of Pharmacy


 

Diuretic action in the kidney

The narrated movie takes the viewer from the human silhouette down subsequent levels of detail finally ending on the transporter proteins which are the direct targets of most diuretic drugs. The movie is intended to show the flow processes within the kidney including such aspects as filtration, reabsorption, and excretion in the nephron. It also shows the molecular sequence of ion transport, how the diuretics inhibit the reabsorption of sodium, and the subsequent effects on other ions.
Created by:

Steven Barbera
Class of 2007
Business/Communications
STA member since 2003

 

Dr. Roberta King
Assistant Professor of Biomedical and Pharmaceutical Sciences
College of Pharmacy

 

Agonists and Antagonists

Click on each topic header along the top in order to view the demonstration.

This interactive animation presents a simple explination of 5 different Agonists and Antagonists: Full Agonist, partial agonist, inverse agonist, competitive agonist, and non-competitve agonist. It was one of the 4 animations prepared for a study on educational innovations at Brown University.

Created by:

Nelson Caetano
Class of 2007
Pharmacy

 

 

 

Dr. Jef Bratberg

Clinical Assistant Professor of Pharmacy Practice

College of Pharmacy



Acid and Base Interactions

Click on the (up) and (down) arrows in order to lower or raise the pH of the environment.

This interactive animation demonstrates the protonation and deprotonation of acidic and basic drugs within a weakly acid or weakly basic environment. This animation was 1 in a series of 4 utilized in a study of educational innovations at Brown University.

Created by:

Nelson Caetano
Class of 2007
Pharmacy

 

 

 

Dr. Jef Bratberg

Clinical Assistant Professor of Pharmacy Practice

College of Pharmacy



Prozac: Selective Serotonin Reuptake Inhibitor (SSRI)

This animation shows how Prozac® alleviates depression. It can also be used to illustrate in general how neuron cells communicate with each other and how a neurotransmitter sends a signal from one neuron to another.

Some people with depression have a shortage of serotonin, the “mood” neurotransmitter in the brain. The antidepressant Prozac®, a Selective Serotonin Reuptake Inhibitor (SSRI), can help correct this imbalance by increasing the brain's own supply of serotonin.

This animation shows how Prozac® acts as a selective inhibitor of Serotonin Reuptake Transporter Protein, thus alleviating depression. In the brain, serotonin is associated with transmission of thoughts and feelings. In a healthy person, an optimal concentration of serotonin is available at the synapse. The imbalance of this neurotransmitter triggers emotional symptoms, like depressed mood, or physical symptoms, like aches and pains.

The blue colored layers represent the trans-membrane structure of both pre- and post-synaptic areas (the upper and lower part of the screen, respectively). Red colored masses in the post-synaptic membrane represent serotonin receptors. There are other membrane proteins as well. Depression can occur when the serotonin transporter protein (a G-protein coupled receptor; shown in white in the pre-synaptic membrane) takes up a serotonin molecule before it has a chance to bind to the post-synaptic receptor. This process is known as reuptake. Prozac® blocks the reuptake of serotonin by disabling the transporter proteins. Consequently, more serotonin molecules will be available to the post-synaptic receptor and thus depression is relieved.

 

Created by:

Joshua Sisson
Class of 2005
Electrical Engineering
STA member since 2001

 

 

Dr. Bongsup Cho
Professor of Biomedical and Pharmaceutical Sciences
College of Pharmacy

 

 

AZT’s Mechanism of Antiviral Activity

This animation shows the chemical details of how the antiviral drug AZT acts as a chain terminator in replicating DNA. The term “chain terminator” is a difficult concept to explain to those students who do not have a good grasp of nucleic acid chemistry. It is important to understand the exact mechanisms of DNA replication at the atomic resolution level as a prerequisite for understanding AZT action. This animation helps the students to visualize the whole chemical process of chain termination.

This animation consists of four small segments and shows how a normal strand of DNA unravels in preparation for replication.

In the next part of the animation, two base pairs are added to a growing DNA strand. Worth noting here is the fact that each new base pair is attacked by the 3’-OH on the existing DNA strand. This OH group attacks the incoming base pair’s a-phosphate group, leading to the formation of a bond between the incoming base pair and the growing DNA strand while causing the release of a diphosphate group.

In the third segment of the animation, AZT is converted by kinases to AZT-monophosphate (AZT-P), AZT-diphosphate (AZT-PP), and AZT-triphosphate (AZT-PPP), respectively. This step must occur in vivo so that AZT can be successfully incorporated into the replicating strand of DNA.

In the final portion of the animation, AZT-PPP is added to the strand. However, AZT lacks the 3’-OH. Instead, it contains N3 at this critical position. Consequently, once it is added, replication comes to a halt. This fact is illustrated in the final segment of the animation where the two base pairs approach the growing strand but are turned away. Therefore, once added to the growing DNA strand, AZT causes DNA chain termination. In doing so, it disrupts the virus’ mechanism for replication and survival.

 

Created by:

Mike Hanley
Class of 2007
Pharmacy

 

 

Dr. Keykavous Parang
Assistant Professor
Biomedical and Pharmaceutical Sciences
College of Pharmacy

 


G Protein Receptor

This animation describes what takes place with a G protein receptor. G Protein Coupled Receptors (GPCRs) are proteins embedded in the surface of cells. GPCRs comprise the largest superfamily of proteins in the body. More than 1,000 different GPCRs have been identified since the first receptors were cloned. These proteins receive chemical signals from outside the cell and pass the signal into the cell, so that the cell can respond to the signal. The structures of the endogenous ligands for GPCRs are exceptionally diverse. They include biogenic amines such as norephnephrine and serotonine, peptides, glycoproteins, lipids, nucleotides, ions, and proteases. The sensation of exogenous stimuli, such as light, odors, and taste, is also mediated by this class of receptors. Activation of the receptor causes an effector inside the cell to produce a second signal chemical, which eventually triggers the cell to react to the original external chemical signal. Andrea and Richard animated the signal process in this clip.

A ligand, in this case Norepinepherine (NE), binds to the receptor and induces a conformational change. This conformational change activates the a/b complex. The complex is bound to GDP while it is inactive.

GTP replaces GDP, thus activating the Alpha subunit. The activated Alpha subunit undergoes a conformational change and activates Adenylate Cyclase.

Once the Adenylate Cyclase is activated, it is then able to convert ATP. The products of ATP conversion are c-AMP and two phosphate molecules. c-AMP is a second messenger used in many processes required for cell survival and growth.

Future plans are to expand this animation to show the second messenger pathways, and further explain intracellular signaling in a variety of living processes.

 

Created by:

Andrea Dichele
Class of 2006
Pharmacy

 

 

Richard Wallace
Class of 2006
Pharmacy




Inner Workings of Enzyme Cytochrome P-450 2C9

This animation shows an 'inside view' of the workings of the enzyme cytochrome P-450 2C9.

The protein, represented by the ribbon and yellow spheres, is from an x-ray crystal structure of a drug metabolizing enzyme called cytochrome P-450 2C9. The larger of the two ligands (clusters of spheres) is the heme group, which acts as cofactor to assist in the catalytic reaction. The smaller of the two ligands is the drug warfarin (an anticoagulant) which is the substrate for the catalytic reaction.

First both ligands are bound. Then the warfarin molecule moves from solution (outside the protein) and finds a channel by which to access its specific binding site. The warfarin molecule finds its way through the channel to find its preferred binding position near the active site.

This model will now be used to illustrate how different drugs interact with this enzyme, and thus interfere with optimum warfarin therapy, a common clinical problem.

 

 

Created by:

Steven Barbera
Class of 2007
Business/Communications
STA member since 2003

 

 

Dr. Roberta King
Assistant Professor of Biomedical and Pharmaceutical Sciences
College of Pharmacy




Drug Absorption and Deprotonation (Aspirin) Animation

This simple animation illustrates how an acidic molecule like aspirin can change its polarity depending on the environment.

Aspirin, which is non-ionized in the strongly acidic stomach environment (pH ~2), can be readily absorbed across the membrane. Once in the bloodstream (pH 7.4), however, the aspirin molecule is deprotonated to become ionic, polar, and thus water soluble and more able to travel to target sites. The deprotonation is indicated by the removal of a hydrogen atom (white sphere) when the aspirin molecule is taken into the bloodstream.

 

 

 

 

 

 

 


Created by:

Joshua Sisson
Class of 2005
Electrical Engineering

 

 

Dr. Bongsup Cho
Professor of Biomedical and Pharmaceutical Sciences
College of Pharmacy




Signal Transduction

This animation describes how growth factors bind to a membrane-bound receptor and triggers a cascade of downstream transduction processes.

Cell behavior is governed by the effects of growth factors which interact with membrane-bound glycoprotein receptors that transduce the first message into a series of intracellular signals that in turn promote or inhibit the transcription expression of specific genes. Cancer cells adopt two principal signaling strategies between cells: endocrine signaling and paracrine signaling. Aside from growth factors, lipophilic hormones such as steroids and thyroid hormone are potent regulators of cell behavior, and may cancers are either hormone-dependent or are responsive to hormone therapy. In the prevention of breast cancer, steroid hormone analogs such as tamoxifen are used to mimic the action of the natural estrogen, eliciting a much weaker estrogenic response. This animation is general in scope, so it can be used in various different lecture contexts.

 

 

Created by:

Steve Huang
Class of 2004
Mechanical Engineering
STA member since 2001

Dr. Bongsup Cho
Professor of Biomedical and Pharmaceutical Sciences
College of Pharmacy