Medicinal and Pharmaceutical Chemistry Commons^™

Genome-Wide Mutagenesis To Investigate The N-Terminal Methylome: The Protective Effects Of Hsp31 And Other Methylated Proteins In Yeast, James Rooney, Jacob Lindsey

The Journal of Purdue Undergraduate Research

The purpose of this study was to understand the role of methylation in regulating the cellular stress response of Hsp31 in Saccharomyces cerevisiae yeast cells. Hsp31 is known to be methylated by the N-terminal methyltransferase Tae1. Changing the methylation site can affect the methylation status of Hsp31, which may play a role in the protective activity of Hsp31 against cellular stress. GLO1 is a gene in yeast involved in catalyzing the detoxification of methylglyoxal (MGO), which is a by-product of glycolysis. We established that S. cerevisiae in the glo1Δ and background is sensitive to cellular stress by MGO. Mutant strains …

Development Of An Imaging Analysis Algorithm For Fluorescence-Based High Content Screening In Parkinson’S Disease, Ryan Arlinghaus

The Journal of Purdue Undergraduate Research

No abstract provided.

A Pharmacological Model Of Trpa1-Mediated Nociception In Zebrafish For Therapeutic Discovery, Emre Coskun

The Journal of Purdue Undergraduate Research

No abstract provided.

Targeting Neuropeptides To Bone Fractures For Accelerated Healing, Nicholas A. Young, Jeffery J. Nielsen, Philip S. Low

The Summer Undergraduate Research Fellowship (SURF) Symposium

In patients over the age of 65 especially, bone fractures represent a significant disease burden. Non-invasive drug therapies are not available for bone fractures which represents a problem for this population. Vasoactive intestinal peptide (VIP) and Pituitary Adenylate Cyclase-Activating Polypeptide (PACAP), two neuromodulator peptides in the glucagon superfamily, have demonstrated positive regulation of osteoblast proliferation and activity. Using acidic oligopeptides, we have developed ligands that target to and accumulate at fracture sites. These targeting ligands can be synthesized in sequence with bone anabolic peptides to minimize off target effects and increase potency at the fracture site to create safer and …

Finding Human Proteins That Bind To A Lassa Virus Protein, Maria Alejandra Pardo Ruge, Veronica J. Heintz, Douglas J. Lacount

The Summer Undergraduate Research Fellowship (SURF) Symposium

Viral hemorrhagic fevers are severe illnesses caused by many different viruses. Lassa Virus is one of these important pathogens in Western Africa, causing hemorrhagic fever and eventually death without early medical treatment. There is no vaccine and there is little information on host-pathogen interactions. Therefore, the interaction between viral proteins and host targets is useful to understand Lassa virus’s lifecycle and pathology, and to develop ways to prevent infection. In this project, we study the nucleoprotein of Lassa virus (NP), which has been reported to have anti-interferon (IFN) activity through elimination of double stranded RNA (dsRNA). These features could be …

Exploring The Effect Of Solution Speciation On Crystallization Outcome, David M. Harvey, Arjun Kalra, Tonglei Li

The Summer Undergraduate Research Fellowship (SURF) Symposium

In the field of pharmaceuticals, the crystallization process significantly impacts the purity, morphology and polymorphism of active pharmaceutical ingredients (API), all of which are important in drug development. Polymorphism is the existence of more than one solid-state form of the same chemical entity. Tolfenamic acid (TFA), a Non-Steroid Anti-inflammatory drug (NSAID), has been shown to exhibit a unique physical phenomenon called concomitant polymorphism, whereby two polymorphs crystallize from the solution simultaneously. From previous work, it has been established that solution speciation i.e. the presence of monomers or dimers of TFA in solution is concentration and temperature dependent. This study correlates …

A Genome-Wide Association Study Identifies A Locus On Tert For Mean Telomere Length In Han Chinese., Yun Liu, Lan Cao, Zhiqiang Li, Daizhan Zhou, Wanqing Liu, Qin Shen, Yanting Wu, Dan Zhang, Xun Hu, Ting Wang, Junyi Ye, Xiaoling Weng, Hong Zhang, Di Zhang, Zhou Zhang, Fatao Liu, Lin He, Yongyong Shi

Borch Department of Medicinal Chemistry and Molecular Pharmacology Faculty Publications

Leukocyte telomere length (LTL) is a predictor of aging and a number of age-related diseases. We performed genome-wide association studies of mean LTL in 2632 individuals,with a two-stage replication in 3917 individuals from Chinese populations. To further validate our findings, we get the results of 696 samples from a cohort of European ancestry. We identified two loci associated with LTL that map in telomerase reverse transcriptase (TERT; rs2736100, P = 1.93×10−5) on chromosome 5p15.33 and near keratin 80 (KRT80; rs17653722, P = 6.96×10−6) on 12q13.13. In Chinese population each C allele of rs2736100 and T allele …

Structure Based Identification And Characterization Of Flavonoids That Disrupt Human Papillomavirus-16 E6 Function, Elliot J. Androphy, Jonathan J. Cherry, Anne Rietz, Anna Malinkevich, Yuqi Liu, Meng Xie, Matthew D. Bartolowits, Vincent J. Davisson, James D. Baleja

Department of Medicinal Chemistry and Molecular Pharmacology Graduate Student Publications

Expression and function of the human papillomavirus (HPV) early protein 6 (E6) is necessary for viral replication and oncogenesis in cervical cancers. HPV E6 targets the tumor suppressor protein p53 for degradation. To achieve this, “high-risk” HPV E6 proteins bind to and modify the target specificity of the ubiquitin ligase E6AP (E6 associated protein). This E6-dependent loss of p53 enables the virus to bypass host cell defenses and facilitates virally induced activation of the cell cycle progression during viral replication. Disruption of the interaction between E6 and E6AP and stabilization of p53 should decrease viability and proliferation of HPV positive …

Investigating Intermolecular Interactions In Crystalline Aspirin Using Cdft, Nicholas Turner, Tonglei Li, Mingtao Zhang

The Summer Undergraduate Research Fellowship (SURF) Symposium

Drugs today are widely administered in their crystalline form, namely via tablets and capsules. The crystal structure of a drug molecule affects important drug qualities such as solubility, bioavailability, shelf life, and compaction properties. In order to form a basis for crystal structure prediction, it is necessary to first understand how intermolecular interactions cause molecules to pack in certain ways. Being able to predict and perhaps even control a drug molecule’s crystal structure will lead to the development of higher quality drugs that perform more consistently. Scientists and engineers do not fully understand the reasons for a molecule assuming a …

Solvent Dependency Of The Uv-Vis Spectrum Of Indenoisoquinolines: Role Of Keto-Oxygens As Polarity Interaction Probes., Andrea Coletta, Silvia Castelli, Giovanni Chillemi, Nico Sanna, Mark S. Cushman, Yves Pommier, Alessandro Desideri

Borch Department of Medicinal Chemistry and Molecular Pharmacology Faculty Publications

Indenoisoquinolines are the most promising non-campthotecins topoisomerase IB inhibitors. We present an integrated experimental/computational investigation of the UV-Vis spectra of the IQNs parental compound (NSC314622) and two of its derivatives (NSC724998 and NSC725776) currently undergoing Phase I clinical trials. In all the three compounds a similar dependence of the relative absorption intensities at 270 nm and 290 nm on solvent polarity is found. The keto-oxygens in positions 5 and 11 of the molecular scaffold of the molecule are the principal chromophores involved in this dependence. Protic interactions on these sites are also found to give rise to absorptions at wavelengthsolution, …

Synthesis And Biological Evaluation Of Novel Folic Acid Receptor-Targeted, Β-Cyclodextrin-Based Drug Complexes For Cancer Treatment., Juan-Juan Yin, Sonali Sharma, Stepan P. Shumyak, Zhi-Xin Wang, Zhi-Wei Zhou, Yangde Zhang, Peixuan Guo, Chen-Zhong Li, Jagat R. Kanwar, Tianxin Yang, Shyam S. Mohapatra, Wanqing Liu, Wei Duan, Jian-Cheng Wang, Qi Li, Xueji Zhang, Jun Tan, Lee Jia, Jun Liang, Ming Q. Wei, Xiaotian Li, Shu-Feng Zhou

Borch Department of Medicinal Chemistry and Molecular Pharmacology Faculty Publications

Drug targeting is an active area of research and nano-scaled drug delivery systems hold tremendous potential for the treatment of neoplasms. In this study, a novel cyclodextrin (CD)-based nanoparticle drug delivery system has been assembled and characterized for the therapy of folate receptor-positive [FR(+)] cancer. Water-soluble folic acid (FA)-conjugated CD carriers (FACDs) were successfully synthesized and their structures were confirmed by 1D/2D nuclear magnetic resonance (NMR), matrix-assisted laser desorption ionization time-of-flight mass spectrometer (MALDI-TOF-MS), high performance liquid chromatography (HPLC), Fourier transform infrared spectroscopy (FTIR), and circular dichroism. Drug complexes of adamatane (Ada) and cytotoxic doxorubicin (Dox) with FACD were readily …

Epigenetic Regulation Of Bmp2 By 1,25-Dihydroxyvitamin D3 Through Dna Methylation And Histone Modification., Baisheng Fu, Hongwei Wang, Jinhua Wang, Ivana Barouhas, Wanqing Liu, Adam Shuboy, David A. Bushinsky, Dongsheng Zhou, Murray J. Favus

Borch Department of Medicinal Chemistry and Molecular Pharmacology Faculty Publications

Genetic hypercalciuric stone-forming (GHS) rats have increased intestinal Ca absorption, decreased renal tubule Ca reabsorption and low bone mass, all of which are mediated at least in part by elevated tissue levels of the vitamin D receptor (VDR). Both 1,25-dihydroxyvitamin D3(1,25(OH)2D3) and bone morphogenetic protein 2 (BMP2) are critical for normal maintenance of bone metabolism and bone formation, respectively. The complex nature of bone cell regulation suggests a potential interaction of these two important regulators in GHS rats. In the present study, BMP2 expression is suppressed by the VDR-1,25(OH)2D3 complex in Bone Marrow Stromal Cells (BMSCs) from GHS and SD …

Binding Of An Indenoisoquinoline To The Topoisomerase-Dna Complex Induces Reduction Of Linker Mobility And Strengthening Of Protein-Dna Interaction., Giordano Mancini, Ilda D'Annessa, Andrea Coletta, Giovanni Chillemi, Yves Pommier, Mark S. Cushman, Alessandro Desideri

Borch Department of Medicinal Chemistry and Molecular Pharmacology Faculty Publications

Long-duration comparative molecular dynamics simulations of the DNA-topoisomerase binary and DNA-topoisomerase-indenoisoquinoline ternary complexes have been carried out. The analyses demonstrated the role of the drug in conformationally stabilizing the protein-DNA interaction. In detail, the protein lips, clamping the DNA substrate, interact more tightly in the ternary complex than in the binary one. The drug also reduces the conformational space sampled by the protein linker domain through an increased interaction with the helix bundle proximal to the active site. A similar alteration of linker domain dynamics has been observed in a precedent work for topotecan but the molecular mechanisms were different …

Plk1 Phosphorylation Of Orc2 And Hbo1 Contributes To Gemcitabine Resistance In Pancreatic Cancer, Bing Song, X Shawn Liu, Steven J. Rice, Shihuan Kuang, Bennett D. Elzey, Stephen F. Konieczny, Timoty L. Ratliff, Tony R. Hazbun, Elena G. Chiorean, Xiaoqi Liu

Borch Department of Medicinal Chemistry and Molecular Pharmacology Faculty Publications

Although gemcitabine is the standard chemotherapeutic drug for treatment of pancreatic cancer, almost all patients eventually develop resistance to this agent. Previous studies identified Polo-like kinase 1 (Plk1) as the mediator of gemcitabine resistance, but the molecular mechanism remains unknown. In this study, we show that Plk1 phosphorylation of Orc2 and Hbo1 mediates the resistance to gemcitabine. We show that the level of Plk1 expression positively correlates with gemcitabine resistance, both in pancreatic cancer cells and xenograft tumors. Overexpression of Plk1 increases gemcitabine resistance, while inhibition of Plk1 sensitizes pancreatic cancer cells to gemcitabine treatment. To validate our findings, we …

Portable Bacterial Identification System Based On Elastic Light Scatter Patterns, Euiwon Bae, Dawei Ying, Donald Kramer, Valery Patsekin, Bartek Rajwa, Cheryl Holdman, Jennifer Sturgis, Vincent J. Davisson, J Paul Robinson

Borch Department of Medicinal Chemistry and Molecular Pharmacology Faculty Publications

Background

Conventional diagnosis and identification of bacteria requires shipment of samples to a laboratory for genetic and biochemical analysis. This process can take days and imposes significant delay to action in situations where timely intervention can save lives and reduce associated costs. To enable faster response to an outbreak, a low-cost, small-footprint, portable microbial-identification instrument using forward scatterometry has been developed.

Results

This device, weighing 9 lb and measuring 12 × 6 × 10.5 in., utilizes elastic light scatter (ELS) patterns to accurately capture bacterial colony characteristics and delivers the classification results via wireless access. The overall system consists of …

Anti-Malarial Activity Of Geldanamycin Derivatives In Mice Infected With Plasmodium Yoelii, Rubul Mout, Zhi-Dong Xu, Angela Kh Wolf, Vincent J. Davisson, Gotam K. Jarori

Borch Department of Medicinal Chemistry and Molecular Pharmacology Faculty Publications

Background

Geldanamycin (GA), a benzoquinone ansamycin antibiotic has been shown in vitro to possess anti-plasmodial activity. Pharmacological activity of this drug is attributed to its ability to inhibit PfHSP90. The parasite growth arrest has been shown to be due to drug-induced blockage of the transition from ring to trophozoite stage. To further evaluate the consequences of this pharmacodyamic feature, the anti-malarial activity of GA analogs with enhanced drug properties in a Plasmodium-infected animal model have been evaluated for their capacity to induce clearance of the parasite. In the process, a hypothesis was subsequently tested regarding the susceptibility of the …

A Synergistic Antiproliferation Effect Of Curcumin And Docosahexaenoic Acid In Sk-Br-3 Breast Cancer Cells: Unique Signaling Not Explained By The Effects Of Either Compound Alone., Jeffrey D. Altenburg, Andrew A. Bieberich, Colin Terry, Kevin A. Harvey, Justin F. Vanhorn, Zhidong Xu, Vincent J. Davisson, Rafat A. Siddiqui

Borch Department of Medicinal Chemistry and Molecular Pharmacology Faculty Publications

Background

Breast cancer is a collection of diseases in which molecular phenotypes can act as both indicators and mediators of therapeutic strategy. Therefore, candidate therapeutics must be assessed in the context of multiple cell lines with known molecular phenotypes. Docosahexaenoic acid (DHA) and curcumin (CCM) are dietary compounds known to antagonize breast cancer cell proliferation. We report that these compounds in combination exert a variable antiproliferative effect across multiple breast cell lines, which is synergistic in SK-BR-3 cells and triggers cell signaling events not predicted by the activity of either compound alone.

Methods

Dose response curves for CCM and DHA …

Challenges Predicting Ligand-Receptor Interactions Of Promiscuous Proteins: The Nuclear Receptor Pxr., Sean Ekins, Sandhya Kortagere, Manisha Iyer, Erica J. Reschly, Markus A. Lill, Matthew R. Redinbo, Matthew D. Krasowski

Borch Department of Medicinal Chemistry and Molecular Pharmacology Faculty Publications

Transcriptional regulation of some genes involved in xenobiotic detoxification and apoptosis is performed via the human pregnane X receptor (PXR) which in turn is activated by structurally diverse agonists including steroid hormones. Activation of PXR has the potential to initiate adverse effects, altering drug pharmacokinetics or perturbing physiological processes. Reliable computational prediction of PXR agonists would be valuable for pharmaceutical and toxicological research. There has been limited success with structure-based modeling approaches to predict human PXR activators. Slightly better success has been achieved with ligand-based modeling methods including quantitative structure-activity relationship (QSAR) analysis, pharmacophore modeling and machine learning. In this …

A Protein Interaction Map Of The Mitotic Spindle, Jonathan Wong, Yuko Nakajima, Stefan Westermann, Ching Shang, Jung-Seog Kang, Crystal Goodner, Pantea Houshmand, Stanley Fields, Clarence S.M. Chan, David Drubin, Georjana Barnes, Tony R. Hazbun

Borch Department of Medicinal Chemistry and Molecular Pharmacology Faculty Publications

The mitotic spindle consists of a complex network of proteins that segregates chromosomes in eukaryotes. To strengthen our understanding of the molecular composition, organization, and regulation of the mitotic spindle, we performed a system-wide two-hybrid screen on 94 proteins implicated in spindle function in Saccharomyces cerevisiae. We report 604 predominantly novel interactions that were detected in multiple screens, involving 303 distinct prey proteins. We uncovered a pattern of extensive interactions between spindle proteins reflecting the intricate organization of the spindle. Furthermore, we observed novel connections between kinetochore complexes and chromatin-modifying proteins and used phosphorylation site mutants of NDC80/TID3 to gain …

Riboflavin Synthase Of Schizosaccharomyces Pombe. Protein Dynamics Revealed By 19f Nmr Protein Perturbation Experiments., Markus Fischer, Ann-Kathrin Schott, Kristina Kemter, Richard Feicht, Gerald Richter, Boris Illarionov, Wolfgang Eisenreich, Stefan Gerhardt, Mark S. Cushman, Stefan Steinbacher, Robert Huber, Adelbert Bacher

Borch Department of Medicinal Chemistry and Molecular Pharmacology Faculty Publications

Background

Riboflavin synthase catalyzes the transformation of 6,7-dimethyl-8-ribityllumazine into riboflavin in the last step of the riboflavin biosynthetic pathway. Gram-negative bacteria and certain yeasts are unable to incorporate riboflavin from the environment and are therefore absolutely dependent on endogenous synthesis of the vitamin. Riboflavin synthase is therefore a potential target for the development of antiinfective drugs.

Results

A cDNA sequence from Schizosaccharomyces pombe comprising a hypothetical open reading frame with similarity to riboflavin synthase of Escherichia coli was expressed in a recombinant E. coli strain. The recombinant protein is a homotrimer of 23 kDa subunits as shown by sedimentation equilibrium …