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- Chemistry (12)
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Articles 1 - 30 of 264
Full-Text Articles in Physical Sciences and Mathematics
Biochemical And Structural Analysis Of The Bacterial Enzyme Succinyl-Diaminopimelate Desuccinylase (Dape) From Acinetobacter Baumannii, Emma H. Kelley, George Minasov, Katherine Konczak, Ludmilla Shuvalova, Joseph S. Brunzelle, Shantanu Shukla, Megan Beulke, Teerana Thabthimthong, Ken W. Olsen, Nicole L. Inniss, Karla Jf Satchell, Daniel P. Becker Ph.D.
Biochemical And Structural Analysis Of The Bacterial Enzyme Succinyl-Diaminopimelate Desuccinylase (Dape) From Acinetobacter Baumannii, Emma H. Kelley, George Minasov, Katherine Konczak, Ludmilla Shuvalova, Joseph S. Brunzelle, Shantanu Shukla, Megan Beulke, Teerana Thabthimthong, Ken W. Olsen, Nicole L. Inniss, Karla Jf Satchell, Daniel P. Becker Ph.D.
Chemistry: Faculty Publications and Other Works
There is an urgent need for new antibiotics given the rise of antibiotic resistance, and succinyl-diaminopimelate desuccinylase (DapE, E.C. 3.5.1.18) has emerged as a promising bacterial enzyme target. DapE from Haemophilus influenzae (HiDapE) has been studied and inhibitors identified, but it is essential to explore DapE from different species to assess selective versus broad-spectrum therapeutics. We have determined the structure of DapE from the ESKAPE pathogen Acinetobacter baumannii (AbDapE) and studied inhibition by known inhibitors of HiDapE. AbDapE is inhibited by captopril and sulfate comparable to HiDapE, but AbDapE was not significantly …
Cyclobutanone Inhibitors Of Diaminopimelate Desuccinylase (Dape) As Potential New Antibiotics, Thahani Shifna Habeeb Mohammad, Emma H. Kelley, Cory T. Reidl Dr., Katherine Konczak, Megan Beulke, Janielle Javier, Ken W. Olsen, Daniel P. Becker Ph.D.
Cyclobutanone Inhibitors Of Diaminopimelate Desuccinylase (Dape) As Potential New Antibiotics, Thahani Shifna Habeeb Mohammad, Emma H. Kelley, Cory T. Reidl Dr., Katherine Konczak, Megan Beulke, Janielle Javier, Ken W. Olsen, Daniel P. Becker Ph.D.
Chemistry: Faculty Publications and Other Works
Based on our previous success in using cyclobutanone derivatives as enzyme inhibitors, we have designed and prepared a 37-member library of α-aminocyclobutanone amides and sulfonamides, screened for inhibition of the bacterial enzyme diaminopimelate desuccinylase (DapE), which is a promising antibiotic target, and identified several inhibitors with micromolar inhibitory potency. Molecular docking suggests binding of the deprotonated hydrate of the strained cyclobutanone, and thermal shift analysis with the most potent inhibitor (3y, IC50 = 23.1 µM) enabled determination of a Ki value of 10.2 +/− 0.26 µM and observed two separate Tm values for H. influenzae DapE (HiDapE).
Design And Synthesis Of N-Succinyl-L,L-2.6-Diaminopimelic Acid Desuccinylase Inhibitors As Potential Novel Antibiotics, Thomas Dipuma
Design And Synthesis Of N-Succinyl-L,L-2.6-Diaminopimelic Acid Desuccinylase Inhibitors As Potential Novel Antibiotics, Thomas Dipuma
Master's Theses
N-Succinyl-L,L-2,6-Diaminopimelic Acid Desuccinylase (DapE) is a bacterial enzyme located in the lysine biosynthetic pathway of all Gram-negative and most Gram-positive species of bacteria including the notorious ESKAPE pathogens, or pathogenic strains of bacteria that have developed significant levels of resistance to currently available antibiotics. As a means to combat this challenge of growing antimicrobial resistance, we have identified the bacterial enzyme DapE as a conserved, novel enzymate target within these resistant bacterial strains,as DapE is responsible for the production of m-DAP and lysine which are ultimately employed in bacterial cell wall synthesis. The overall aim of this research is to …
A Critical Inter-Subunit Interaction For The Transmission Of The Allosteric Signal In The Agrobacterium Tumefaciens Adp-Glucose Pyrophosphorylase, Hiral Patel, Gabriela Martinez-Ramirez Ms., Emily Dobrzynski, Alberto A. Iglesias, Dali Liu, Miguel Ballicora
A Critical Inter-Subunit Interaction For The Transmission Of The Allosteric Signal In The Agrobacterium Tumefaciens Adp-Glucose Pyrophosphorylase, Hiral Patel, Gabriela Martinez-Ramirez Ms., Emily Dobrzynski, Alberto A. Iglesias, Dali Liu, Miguel Ballicora
Chemistry: Faculty Publications and Other Works
ADP-glucose pyrophosphorylase is a key regulatory enzyme involved in starch and glycogen synthesis in plants and bacteria, respectively. It has been hypothesized that inter-subunit communications are important for the allosteric effect in this enzyme. However, no specific interactions have been identified as part of the regulatory signal. The enzyme from Agrobacterium tumefaciens is a homotetramer allosterically regulated by fructose 6-phosphate and pyruvate. Three pairs of distinct subunit-subunit interfaces are present. Here we focus on an interface that features two symmetrical interactions between Arg11 and Asp141 from one subunit with residues Asp141 and Arg11 of the neighbor subunit, respectively. Previously, scanning …
Carborane-Containing Hydroxamate Mmp Ligands For The Treatment Of Tumors Using Boron Neutron Capture Therapy (Bnct): Efficacy Without Tumor Cell Entry, Sebastian Flieger, Mao Takagaki, Natsuko Kondo, Marlon Lutz Jr., Yash Gupta, Hiroki Ueda, Yoshinori Sakurai, Graham Moran, Prakasha Kempaiah, Narayan Hosmane, Minoru Suzuki, Daniel P. Becker Ph.D.
Carborane-Containing Hydroxamate Mmp Ligands For The Treatment Of Tumors Using Boron Neutron Capture Therapy (Bnct): Efficacy Without Tumor Cell Entry, Sebastian Flieger, Mao Takagaki, Natsuko Kondo, Marlon Lutz Jr., Yash Gupta, Hiroki Ueda, Yoshinori Sakurai, Graham Moran, Prakasha Kempaiah, Narayan Hosmane, Minoru Suzuki, Daniel P. Becker Ph.D.
Chemistry: Faculty Publications and Other Works
New carborane-bearing hydroxamate matrix metalloproteinase (MMP) ligands have been synthesized for boron neutron capture therapy (BNCT) with nanomolar potency against MMP-2, -9 and -13. New analogs are based on MMP inhibitor CGS-23023A, and two previously reported MMP ligands 1 (B1) and 2 (B2) were studied in vitro for BNCT activity. The boronated MMP ligands 1 and 2 showed high in vitro tumoricidal effects in an in vitro BNCT assay, exhibiting IC50 values for 1 and 2 of 2.04 × 10−2 mg/mL and 2.67 × 10−2 mg/mL, respectively. The relative killing effect of 1 to L-boronophenylalanine (BPA) is …
In Silico Binding Of 2-Aminocyclobutanones To Sars-Cov-2 Nsp13 Helicase And Demonstration Of Antiviral Activity, Thahani S. Habeeb Mohammad, Yash Gupta, Cory T. Reidl, Vlad Nicolaescu, Haley Gula, Ravi Durvasula, Prakasha Kempaiah, Daniel P. Becker Ph.D.
In Silico Binding Of 2-Aminocyclobutanones To Sars-Cov-2 Nsp13 Helicase And Demonstration Of Antiviral Activity, Thahani S. Habeeb Mohammad, Yash Gupta, Cory T. Reidl, Vlad Nicolaescu, Haley Gula, Ravi Durvasula, Prakasha Kempaiah, Daniel P. Becker Ph.D.
Chemistry: Faculty Publications and Other Works
The landscape of viral strains and lineages of SARS-CoV-2 keeps changing and is currently dominated by Delta and Omicron variants. Members of the latest Omicron variants, including BA.1, are showing a high level of immune evasion, and Omicron has become a prominent variant circulating globally. In our search for versatile medicinal chemistry scaffolds, we prepared a library of substituted α-aminocyclobutanones from an α-aminocyclobutanone synthon (11). We performed an in silico screen of this actual chemical library as well as other virtual 2-aminocyclobutanone analogs against seven SARS-CoV-2 nonstructural proteins to identify potential drug leads against SARS-CoV-2, and more broadly against coronavirus …
Velocity Map Images Of Desorbing Oxygen From Sub-Surface States Of Rh(111), Arved C. Dorst, Friedrich Güthoff, Daniel Schauermann, Alec M. Wodtke, Daniel Killelea, Tim Schäfer
Velocity Map Images Of Desorbing Oxygen From Sub-Surface States Of Rh(111), Arved C. Dorst, Friedrich Güthoff, Daniel Schauermann, Alec M. Wodtke, Daniel Killelea, Tim Schäfer
Chemistry: Faculty Publications and Other Works
We combine velocity map imaging (VMI) with temperature-programmed desorption (TPD) experiments to record the angular-resolved velocity distributions of recombinatively-desorbing oxygen from Rh(111). We assign the velocity distributions to desorption from specific surface and sub-surface states by matching the recorded distributions to the desorption temperature. These results provide insight into the recombinative desorption mechanisms and the availability of oxygen for surface-catalyzed reactions.
Cultivating Teacher Expertise In The Landscape Of Green Chemistry: The Development Of Pedagogical Content Knowledge In Beyond Benign’S Lead Teacher Program, Philip Charles Nahlik
Cultivating Teacher Expertise In The Landscape Of Green Chemistry: The Development Of Pedagogical Content Knowledge In Beyond Benign’S Lead Teacher Program, Philip Charles Nahlik
Dissertations
Chemistry Education, Green Chemistry, Pedagogical Content Knowledge, Professional Learning Communities, Sustainability, Teacher Training
Investigation Of Carbon Dioxide Oxidation Reaction Pathways On Rh(111) Via Reflection Absorption Infrared Spectroscopy (Rairs), Elizabeth A. Jamka
Investigation Of Carbon Dioxide Oxidation Reaction Pathways On Rh(111) Via Reflection Absorption Infrared Spectroscopy (Rairs), Elizabeth A. Jamka
Dissertations
CO oxidation, RAIRS, Rh(111), Surface Science, UHV
Site-Directed Mutagenesis Of Serine-72 Reveals The Location Of The Fructose 6-Phosphate Regulatory Site Of The Agrobacterium Tumefaciensadp-Glucose Pyrophosphorylase, Mashael Alghamdi Dr., Rania Ali Z Hussien, Yuanzhang Zheng, Hiral Patel, Matias D. Asencion Diez, Alberto A. Iglesias, Dali Liu, Miguel A. Ballicora
Site-Directed Mutagenesis Of Serine-72 Reveals The Location Of The Fructose 6-Phosphate Regulatory Site Of The Agrobacterium Tumefaciensadp-Glucose Pyrophosphorylase, Mashael Alghamdi Dr., Rania Ali Z Hussien, Yuanzhang Zheng, Hiral Patel, Matias D. Asencion Diez, Alberto A. Iglesias, Dali Liu, Miguel A. Ballicora
Chemistry: Faculty Publications and Other Works
The allosteric regulation of ADP–glucose pyrophosphorylase is critical for the biosynthesis of glycogen in bacteria and starch in plants. The enzyme from Agrobacterium tumefaciens is activated by fructose 6-phosphate (Fru6P) and pyruvate (Pyr). The Pyr site has been recently found, but the site where Fru6P binds has remained unknown. We hypothesize that a sulfate ion previously found in the crystal structure reveals a part of the regulatory site mimicking the presence of the phosphoryl moiety of the activator Fru6P. Ser72 interacts with this sulfate ion and, if the hypothesis is correct, Ser72 would affect the interaction with Fru6P and activation …
Temperature-Resolved Surface Infrared Spectroscopy Of Co On Rh(111) And (2 × 1)-O/Rh(111), Elizabeth A. Jamka, Maxwell Z. Gillum, Christina N. Grytsyshyn-Giger, Faith J. Lewis, Daniel Killelea
Temperature-Resolved Surface Infrared Spectroscopy Of Co On Rh(111) And (2 × 1)-O/Rh(111), Elizabeth A. Jamka, Maxwell Z. Gillum, Christina N. Grytsyshyn-Giger, Faith J. Lewis, Daniel Killelea
Chemistry: Faculty Publications and Other Works
Heterogeneously catalyzed reactions over transition metal surfaces are pillars of chemical industry and account for a significant fraction of the global energy demand. CO oxidation provides insight into the relative reactivity of various oxygenaceous surface phases, and it is necessary to first understand where it binds to the surface and the nature of the local environment to develop robust mechanistic pictures of the reaction. Surface IR spectroscopy is a quantitative technique that also provides information about the binding sites and chemical environments of the adsorbed CO molecules. Here, we report results from a study of CO sticking to clean Rh(111) …
Development Of An Analytical Method For Determination Of Lead And Cadmium In Biological Materials By Gfaas Using Escherichia Coli As Model Substance, Michelle Catherine Gende, Martina Schmeling
Development Of An Analytical Method For Determination Of Lead And Cadmium In Biological Materials By Gfaas Using Escherichia Coli As Model Substance, Michelle Catherine Gende, Martina Schmeling
Chemistry: Faculty Publications and Other Works
In this work, an analytical method was developed for the determination of lead and cadmium in biological samples using graphite furnace atomic absorption spectrometry. Escherichia coli (E. coli) was chosen as model substance for this purpose as it is readily available in most laboratories and can be quickly and easily prepared with a high turnaround rate. Four different sample preparation methods were initially evaluated with respect to percent recovery, limit of detection, and limit of quantification, and the most promising one was developed further. The final process involving microwave assisted digestion of the sample with nitric acid …
Carbohydrate Metabolism In Bacteria: Alternative Specificities In Adp-Glucose Pyrophosphorylases Open Novel Metabolic Scenarios And Biotechnological Tools, Jaina A. Bhayani, Maria Josefina Iglesias, Romina I. Minen, Antonela E. Cereijo, Miguel Ballicora, Alberto A. Iglesias, Matias D. Asencion Diez
Carbohydrate Metabolism In Bacteria: Alternative Specificities In Adp-Glucose Pyrophosphorylases Open Novel Metabolic Scenarios And Biotechnological Tools, Jaina A. Bhayani, Maria Josefina Iglesias, Romina I. Minen, Antonela E. Cereijo, Miguel Ballicora, Alberto A. Iglesias, Matias D. Asencion Diez
Chemistry: Faculty Publications and Other Works
We explored the ability of ADP-glucose pyrophosphorylase (ADP-Glc PPase) from different bacteria to use glucosamine (GlcN) metabolites as a substrate or allosteric effectors. The enzyme from the actinobacteria Kocuria rhizophila exhibited marked and distinctive sensitivity to allosteric activation by GlcN-6P when producing ADP-Glc from glucose-1-phosphate (Glc-1P) and ATP. This behavior is also seen in the enzyme from Rhodococcus spp., the only one known so far to portray this activation. GlcN-6P had a more modest effect on the enzyme from other Actinobacteria (Streptomyces coelicolor), Firmicutes (Ruminococcus albus), and Proteobacteria (Agrobacterium tumefaciens) groups. In addition, we …
Repurposing Lansoprazole And Posaconazole To Treat Leishmaniasis: Integration Of In Vitro Testing, Pharmacological Corroboration, And Mechanisms Of Action, Yash Gupta, Steven Goicoechea, Jesus G. Romero, Raman Mathur, Thomas R. Caulfield, Daniel P. Becker, Ravi Durvasula, Prakasha Kempaiah
Repurposing Lansoprazole And Posaconazole To Treat Leishmaniasis: Integration Of In Vitro Testing, Pharmacological Corroboration, And Mechanisms Of Action, Yash Gupta, Steven Goicoechea, Jesus G. Romero, Raman Mathur, Thomas R. Caulfield, Daniel P. Becker, Ravi Durvasula, Prakasha Kempaiah
Chemistry: Faculty Publications and Other Works
Leishmaniasis remains a serious public health problem in many tropical regions of the world. Among neglected tropical diseases, the mortality rate of leishmaniasis is second only to malaria. All currently approved therapeutics have toxic side effects and face rapidly increasing resistance. To identify existing drugs with antileishmanial activity and predict the mechanism of action, we designed a drug-discovery pipeline utilizing both in-silico and in-vitro methods. First, we screened compounds from the Selleckchem Bio-Active Compound Library containing ~1622 FDA-approved drugs and narrowed these down to 96 candidates based on data mining for possible anti-parasitic properties. Next, we completed preliminary in-vitro testing …
Determination Of Dissociation Constants Of Protein Ligands By Thermal Shift Assay, Jaina A. Bhayani, Miguel Ballicora
Determination Of Dissociation Constants Of Protein Ligands By Thermal Shift Assay, Jaina A. Bhayani, Miguel Ballicora
Chemistry: Faculty Publications and Other Works
The thermal shift assay (TSA) is a powerful tool used to detect molecular interactions between proteins and ligands. Using temperature as a physical denaturant and an extrinsic fluorescent dye, the TSA tracks protein unfolding. This method precisely determines the midpoint of the unfolding transition (Tm" role="presentation">), which can shift upon the addition of a ligand. Though experimental protocols have been well developed, the thermal shift assay data traditionally yielded qualitative results. Quantitative methods for Kd" role="presentation"> determination relied either on empirical and inaccurate usage of Tm" role="presentation"> or on isothermal approaches, which do not take full advantage of the …
Iron Dysregulation In Covid-19 And Reciprocal Evolution Of Sars-Cov-2: Natura Nihil Frustra Facit, Yash Gupta, Dawid Maciorowski, Brian Medernach, Daniel P. Becker Ph.D., Ravi Durvasula, Claudia R. Libertin, Prakasha Kempaiah
Iron Dysregulation In Covid-19 And Reciprocal Evolution Of Sars-Cov-2: Natura Nihil Frustra Facit, Yash Gupta, Dawid Maciorowski, Brian Medernach, Daniel P. Becker Ph.D., Ravi Durvasula, Claudia R. Libertin, Prakasha Kempaiah
Chemistry: Faculty Publications and Other Works
After more than a year of the COVID-19 pandemic, SARS-CoV-2 infection rates with newer variants continue to devastate much of the world. Global healthcare systems are overwhelmed with high positive patient numbers. Silent hypoxia accompanied by rapid deterioration and some cases with septic shock is responsible for COVID-19 mortality in many hospitalized patients. There is an urgent need to further understand the relationships and interplay with human host components during pathogenesis and immune evasion strategies. Currently, acquired immunity through vaccination or prior infection usually provides sufficient protection against the emerging variants of SARS-CoV-2 except Omicron variant requiring recent booster. New …
Synthesis And Characterization Of Ruthenium Complexes And Their Potential And Photosensitizers For Photodynamic Therapy, Keit Dine
Master's Theses
Cancer is one of the leading causes of death in the world with over 10 million people dying of the disease every year. Inorganic complexes supported by platinum metal centers are often used in cancer treatment. However, these complexes lack selectivity for tumor cells. As such, other alternatives to platinum have been explored. Ruthenium (Ru) complexes are one of the most promising candidates due to their ability to be used as photosensitizing drugs in photodynamic therapy. Herein, we report the design, synthesis, and characterization of two novel ruthenium-based complexes. One compound is a Ru(II) homoleptic complex, while the other is …
Rhodium-Catalyzed Decarbonylation Of Aroyl Chlorides, Wiktoria M. Koza
Rhodium-Catalyzed Decarbonylation Of Aroyl Chlorides, Wiktoria M. Koza
Dissertations
The development of efficient strategies for the synthesis of aryl–halogen bonds is highly desirable due to the prevalence of these moieties in pharmaceuticals, agrochemicals, and organic synthesis. Although there are numerous applications of aryl chlorides in chemistry, an efficient strategy for the preparation of these molecules is underdeveloped. Transition metal-catalyzed decarbonylation provides an efficient and selective approach for aryl–halogen bond formation. There has been significant progress in the development of new decarbonylation strategies, particularly involving aldehydes for the synthesis of new carbon–hydrogen (C–H) bonds or for cross-coupling reactions. However, transition metal-catalyzed decarbonylation methods for carbon–halogen (C–X) bond formation have been …
Biocatalytic Intramolecular C−H Aminations Via Engineered Heme Proteins: Full Reaction Pathways And Axial Ligand Effects, Yang Wei, Melissa Conklin, Yong Zhang
Biocatalytic Intramolecular C−H Aminations Via Engineered Heme Proteins: Full Reaction Pathways And Axial Ligand Effects, Yang Wei, Melissa Conklin, Yong Zhang
Chemistry: Faculty Publications and Other Works
Engineered heme protein biocatalysts provide an efficient and sustainable approach to develop amine-containing compounds through C−H amination. A quantum chemical study to reveal the complete heme catalyzed intramolecular C−H amination pathway and protein axial ligand effect was reported, using reactions of an experimentally used arylsulfonylazide with hemes containing L=none, SH−, MeO−, and MeOH to simulate no axial ligand, negatively charged Cys and Ser ligands, and a neutral ligand for comparison. Nitrene formation was found as the overall rate-determining step (RDS) and the catalyst with Ser ligand has the best reactivity, consistent with experimental reports. Both RDS and non-RDS (nitrene transfer) …
Bisindolylmaleimide Ix: A Novel Anti-Sars-Cov2 Agent Targeting Viral Main Protease 3clpro Demonstrated By Virtual Screening Pipeline And In-Vitro Validation Assays, Yash Gupta, Dawid Maciorowski, Samantha E. Zak, Krysten A. Jones, Rahul S. Kathayat, Saara-Anne Azizi, Raman Mathur, Catherine M. Pearce, David J. Ilc, Hamza Husein, Andrew S. Herbert, Ajay Bharti, Brijesh Rathi, Ravi Durvasula, Daniel P. Becker, Bryan C. Dickinson, John M. Dye, Prakasha Kempaiah
Bisindolylmaleimide Ix: A Novel Anti-Sars-Cov2 Agent Targeting Viral Main Protease 3clpro Demonstrated By Virtual Screening Pipeline And In-Vitro Validation Assays, Yash Gupta, Dawid Maciorowski, Samantha E. Zak, Krysten A. Jones, Rahul S. Kathayat, Saara-Anne Azizi, Raman Mathur, Catherine M. Pearce, David J. Ilc, Hamza Husein, Andrew S. Herbert, Ajay Bharti, Brijesh Rathi, Ravi Durvasula, Daniel P. Becker, Bryan C. Dickinson, John M. Dye, Prakasha Kempaiah
Chemistry: Faculty Publications and Other Works
SARS-CoV-2, the virus that causes COVID-19 consists of several enzymes with essential functions within its proteome. Here, we focused on repurposing approved and investigational drugs/compounds. We targeted seven proteins with enzymatic activities known to be essential at different stages of the viral cycle including PLpro, 3CLpro, RdRP, Helicase, ExoN, NendoU, and 2′-O-MT. For virtual screening, energy minimization of a crystal structure of the modeled protein was carried out using the Protein Preparation Wizard (Schrodinger LLC 2020-1). Following active site selection based on data mining and COACH predictions, we performed a high-throughput virtual screen of drugs and investigational molecules (n = …
Oxygen-Induced Surface Reconstructions On Curved Ag(111), Marie Turano, Ludo B. F. Juurlink, Maxwell Z. Gillum, Elizabeth A. Jamka, George Hildebrandt, Faith J. Lewis, Daniel Killelea
Oxygen-Induced Surface Reconstructions On Curved Ag(111), Marie Turano, Ludo B. F. Juurlink, Maxwell Z. Gillum, Elizabeth A. Jamka, George Hildebrandt, Faith J. Lewis, Daniel Killelea
Chemistry: Faculty Publications and Other Works
The adsorption of oxygen and the resultant O-induced surface reconstructions are key components in heterogeneously catalyzed reactions on silver metal surfaces. O uptake and reconstructions on planar Ag(111) are well-characterized, and in this paper, we show that curved Ag(111) features similar O adsorption and reconstructions. Through a systematic scanning tunneling microscope study of a curved Ag(111) single crystal exposed to gas-phase atomic oxygen at a temperature of 525 K, we observed Oad and, upon higher coverages, saw p(4 4) and p(4 5 p3) reconstructions form on both the A-type and B-type steps. Exposures at low temperatures (< 500 K) resulted in the formation of subsurface oxygen and the appearance of a stripe pattern and amorphous phase on the surface. Upon heating, stable surface reconstructions were formed. Although the geometric arrangement of atoms along the steps were different, A-type and B-type steps formed the same reconstructions. In addition, the B-type steps also saw the formation of several different features atop the oxygen reconstructions.
Bridging The 12-6-4 Model And The Fluctuating Charge Model, Pengfei Li
Bridging The 12-6-4 Model And The Fluctuating Charge Model, Pengfei Li
Chemistry: Faculty Publications and Other Works
Metal ions play important roles in various biological systems. Molecular dynamics (MD) using classical force field has become a popular research tool to study biological systems at the atomic level. However, meaningful MD simulations require reliable models and parameters. Previously we showed that the 12-6 Lennard-Jones nonbonded model for ions could not reproduce the experimental hydration free energy (HFE) and ion-oxygen distance (IOD) values simultaneously when ion has a charge of +2 or higher. We discussed that this deficiency arises from the overlook of the ion-induced dipole interaction in the 12-6 model, and this term is proportional to 1/r …
Cyclobutanone Inhibitor Of Cobalt-Functionalized Metallo-Γ-Lactonase Aiia With Cyclobutanone Ring Opening In The Active Site, Cory T. Reidl, Romila Mascarenhas, Thahani S. Habeeb Mohammad, Marlon R. Lutz Jr, Pei W. Thomas, Walter Fast, Dali Liu, Daniel P. Becker Ph.D.
Cyclobutanone Inhibitor Of Cobalt-Functionalized Metallo-Γ-Lactonase Aiia With Cyclobutanone Ring Opening In The Active Site, Cory T. Reidl, Romila Mascarenhas, Thahani S. Habeeb Mohammad, Marlon R. Lutz Jr, Pei W. Thomas, Walter Fast, Dali Liu, Daniel P. Becker Ph.D.
Chemistry: Faculty Publications and Other Works
An α-amido cyclobutanone possessing a C10 hydrocarbon tail was designed as a potential transition-state mimetic for the quorum-quenching metallo-γ-lactonase autoinducer inactivator A (AiiA) with the support of in-house modeling techniques and found to be a competitive inhibitor of dicobalt(II) AiiA with an inhibition constant of Ki = 0.007 ± 0.002 mM. The catalytic mechanism of AiiA was further explored using our product-based transition-state modeling (PBTSM) computational approach, providing substrate-intermediate models arising during enzyme turnover and further insight into substrate–enzyme interactions governing native substrate catalysis. These interactions were targeted in the docking of cyclobutanone hydrates into the active site of …
Gcn5-Related N-Acetyltransferases (Gnats) With A Catalytic Serine Residue Can Play Ping-Pong Too, Jackson T. Baumgartner, Thahani S. Habeeb Mohammad, Mateusz P. Czub, Karolina A. Majorek, Xhulio Arolli, Cillian Variot, Madison Anonick, Wladek Minor, Miguel A. Ballicora, Daniel P. Becker Ph.D., Misty L. Kuhn
Gcn5-Related N-Acetyltransferases (Gnats) With A Catalytic Serine Residue Can Play Ping-Pong Too, Jackson T. Baumgartner, Thahani S. Habeeb Mohammad, Mateusz P. Czub, Karolina A. Majorek, Xhulio Arolli, Cillian Variot, Madison Anonick, Wladek Minor, Miguel A. Ballicora, Daniel P. Becker Ph.D., Misty L. Kuhn
Chemistry: Faculty Publications and Other Works
Enzymes in the Gcn5-related N-acetyltransferase (GNAT) superfamily are widespread and critically involved in multiple cellular processes ranging from antibiotic resistance to histone modification. While acetyl transfer is the most widely catalyzed reaction, recent studies have revealed that these enzymes are also capable of performing succinylation, condensation, decarboxylation, and methylcarbamoylation reactions. The canonical chemical mechanism attributed to GNATs is a general acid/base mechanism; however, mounting evidence has cast doubt on the applicability of this mechanism to all GNATs. This study shows that the Pseudomonas aeruginosa PA3944 enzyme uses a nucleophilic serine residue and a hybrid ping-pong mechanism for catalysis instead …
Atomic-Resolution 1.3 Å Crystal Structure, Inhibition By Sulfate, And Molecular Dynamics Of The Bacterial Enzyme Dape, Matthew Kochert, Boguslaw P. Nocek, Thahani S. Habeeb Mohammad, Elliot Gild, Kaitlyn Lovato, Tahirah K. Heath, Richard C. Holz, Kenneth W. Olsen, Daniel P. Becker Ph.D.
Atomic-Resolution 1.3 Å Crystal Structure, Inhibition By Sulfate, And Molecular Dynamics Of The Bacterial Enzyme Dape, Matthew Kochert, Boguslaw P. Nocek, Thahani S. Habeeb Mohammad, Elliot Gild, Kaitlyn Lovato, Tahirah K. Heath, Richard C. Holz, Kenneth W. Olsen, Daniel P. Becker Ph.D.
Chemistry: Faculty Publications and Other Works
We report the atomic-resolution (1.3 Å) X-ray crystal structure of an open conformation of the dapE-encoded N-succinyl-l,l-diaminopimelic acid desuccinylase (DapE, EC 3.5.1.18) from Neisseria meningitidis. This structure [Protein Data Bank (PDB) entry 5UEJ] contains two bound sulfate ions in the active site that mimic the binding of the terminal carboxylates of the N-succinyl-l,l-diaminopimelic acid (l,l-SDAP) substrate. We demonstrated inhibition of DapE by sulfate (IC50 = 13.8 ± 2.8 mM). Comparison with other DapE structures in the PDB demonstrates the flexibility of the interdomain connections of this protein. This high-resolution structure was then utilized as the …
Exposing The Effects Of Reaction Cavity In Solid-Phase Reaction Kinetics, Michael Carr
Exposing The Effects Of Reaction Cavity In Solid-Phase Reaction Kinetics, Michael Carr
Master's Theses
Reactivity of molecular solids is governed by topochemical considerations, where minimizedmolecular movement dictates both product identity and kinetics. This Thesis explores the central role reaction cavity plays in the topochemical principle by using the highly varied cavities formed by the different facets of a tetracene crystal. The relative rates for ten different reaction cavities were measured via energy dispersive X-ray spectroscopy for the reaction of tetracene with vapors of maleic anhydride. Variance in cavities resulted in Diels-Alder reaction rates that differed by as much as a factor of 2.6. Effects were understood via molecular dynamic simulations which modeled the approach …
Development Of Small Molecule Inhibitors Of Therapeutic Target Enzymes: Paths To Discover Novel Antimicrobials, Thahani Shifna Habeeb Mohammad
Development Of Small Molecule Inhibitors Of Therapeutic Target Enzymes: Paths To Discover Novel Antimicrobials, Thahani Shifna Habeeb Mohammad
Dissertations
The rising antimicrobial resistance to antibiotics is a major global problem, which has been exacerbated by the inappropriate use of antibiotics. The effectiveness of frequently prescribed penicillin derivatives and β-lactamase inhibitors are compromised by the evolution of bacterial β-lactamases and antibiotic-resistant bacteria. Consequently, design and synthesis of small-molecule inhibitors of identified novel antibiotic targets is an urgent unmet medical need. We previously demonstrated that N-functionalized α-aminocyclobutanones can act as peptidomimetic enzyme inhibitors, including inhibition of a key esterase in Francisella Tularensis. The carbonyl of a cyclobutanone is electrophilic due to ring strain, therefore cyclobutanone derivatives can serve as transition state …
Identification Of New Pathways For Co Oxidation On Rh(111) & Spatial And Structural Control Of O-Induced Reconstruction Of Ag(111), Marie Turano
Dissertations
Understanding the fundamentals of oxygen surface structures under a variety of conditions is pivotal to determining reactivity of heterogeneous catalysis. Exposure of catalytically active metal surfaces to high oxygen coverages results in a myriad of surface structures. A further complication is the formation of subsurface oxygen (Osub) or oxygen present in the near subsurface region of the metal. It is known to form in transition metals yet the absorption of oxygen and resultant formation of Osub is not equivalent across all catalytically relevant metals. As a result, it is difficult to predict the stability and efficacy of the formation of …
A Review Of The Preclinical And Clinical Efficacy Of Remdesivir, Hydroxychloroquine, And Lopinavir-Ritonavir Treatments Against Covid-19, Dawid Maciorowski, Samir Z. El Idrissi, Yash Gupta, Brian J. Medernach, Michael B. Burns, Daniel P. Becker Ph.D., Ravi Durvasula, Prakasha Kempaiah
A Review Of The Preclinical And Clinical Efficacy Of Remdesivir, Hydroxychloroquine, And Lopinavir-Ritonavir Treatments Against Covid-19, Dawid Maciorowski, Samir Z. El Idrissi, Yash Gupta, Brian J. Medernach, Michael B. Burns, Daniel P. Becker Ph.D., Ravi Durvasula, Prakasha Kempaiah
Chemistry: Faculty Publications and Other Works
In December of 2019, an outbreak of a novel coronavirus flared in Wuhan, the capital city of the Hubei Province, China. The pathogen has been identified as a novel enveloped RNA beta-coronavirus named severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The virus SARS-CoV-2 is associated with a disease characterized by severe atypical pneumonia known as coronavirus 2019 (COVID-19). Typical symptoms of this disease include cough, fever, malaise, shortness of breath, gastrointestinal symptoms, anosmia, and, in severe cases, pneumonia.1 The high-risk group of COVID-19 patients includes people over the age of 60 years as well as people with existing cardiovascular …
Indoline-6-Sulfonamide Inhibitors Of The Bacterial Enzyme Dape, Cory T. Reidl, Tahirah K. Heath, Iman Darwish, Rachel M. Torrez, Maxwell Moore, Elliot Gild, Boguslaw P. Nocek, Anna Starus, Richard C. Holz, Daniel P. Becker Ph.D.
Indoline-6-Sulfonamide Inhibitors Of The Bacterial Enzyme Dape, Cory T. Reidl, Tahirah K. Heath, Iman Darwish, Rachel M. Torrez, Maxwell Moore, Elliot Gild, Boguslaw P. Nocek, Anna Starus, Richard C. Holz, Daniel P. Becker Ph.D.
Chemistry: Faculty Publications and Other Works
Inhibitors of the bacterial enzyme dapE-encoded N-succinyl-l,l-diaminopimelic acid desuccinylase (DapE; EC 3.5.1.18) hold promise as antibiotics with a new mechanism of action. Herein we describe the discovery of a new series of indoline sulfonamide DapE inhibitors from a high-throughput screen and the synthesis of a series of analogs. Inhibitory potency was measured by a ninhydrin-based DapE assay recently developed by our group. Molecular docking experiments suggest active site binding with the sulfonamide acting as a zinc-binding group (ZBG).