Fiona Kearns

University of South Florida | USF · Department of Chemistry

A selection of antiviral compounds from the Drug Repurposing Hub were screened as potential inhibitors against SARS-CoV-2 protein targets using CIFDock, a flexible docking method. CIFDock allows for a fully flexible active site of the protein-ligand complex and retaining of explicit water molecules throughout docking simulations. This method provid...

A key step during indirect alchemical free energy simulations using quantum mechanical/molecular mechanical (QM/MM) hybrid potential energy functions is the calculation of the free energy difference ΔAlow→high between the low level (e.g., pure MM) and the high level of theory (QM/MM). A reliable approach uses nonequilibrium work (NEW) switching sim...

Phylum Cnidaria has been an excellent source of natural products, with thousands of metabolites identified. Many of these have not been screened in bioassays. The aim of this study was to explore the potential of 5600 Cnidaria natural products (after excluding those known to derive from microbial symbionts), using a systematic approach based on che...

p>Cold water benthic environments are a prolific source of structurally diverse molecules with a range of bioactivity against human disease. Specimens of a previously chemically unexplored soft coral, Drifa sp., were collected during a deep-sea cruise that sampled marine invertebrates along the Irish continental margin in 2018. Tuaimenal A ( 1 ), a...

A pandemic outbreak of a viral respiratory infection (COVID-19) caused by a coronavirus (SARS-CoV-2) prompted a multitude of research focused on various aspects of this disease. One of the interesting aspects of the clinical manifestation of the infection is an accompanying ocular surface viral infection, viral conjunctivitis. Although occasional r...

Gram-negative bacteria expressing class A β-lactamases pose a serious health threat due to their ability to inactivate all β-lactam antibiotics. The acyl–enzyme intermediate is a central milestone in the hydrolysis reaction catalyzed by these enzymes. However, the protonation states of the catalytic residues in this complex have never been fully an...

Compromised PTEN function is associated with multiple cancers. As per the continuum model, variable degree of PTEN inactivation drives distinct cancer phenotypes. Loss of PTEN activity, via genomic/non-genomic mechanisms, leads to enhanced oncogenic PI3K signaling. While kinase inhibitors have proved effective in the clinic, they are increasingly m...

Designing organic saccharide sensors for use in aqueous solution is a non-trivial endeavor. Incorporation of hydrogen bonding groups on a sensor's receptor unit to target saccharides is an obvious strategy, but not one that is likely to ensure analyte-receptor interactions over analyte-solvent or receptor-solvent interactions. Phenylboronic acids a...

Indirect (S)QM/MM free energy simulations (FES) are vital to efficiently incorporating sufficient sampling and accurate (QM) energetic evaluations when estimating free energies of practical/experimental interest. Connecting between levels of theory, i.e., calculating Δ A l o w → h i g h , remains to be the most challenging step within an indirect F...

Significance Synthetic polymers are ubiquitous in the modern world but pose a global environmental problem. While plastics such as poly(ethylene terephthalate) (PET) are highly versatile, their resistance to natural degradation presents a serious, growing risk to fauna and flora, particularly in marine environments. Here, we have characterized the...

We demonstrate that Jarzynski's equation can be used to reliably compute free energy differences between low and high level representations of systems. The need for such a calculation arises when employing the so-called “indirect” approach to free energy simulations with mixed quantum mechanical/molecular mechanical (QM/MM) Hamiltonians; a popular...

In 2000, a novel secondary metabolite (erebusinone, Ereb) was isolated from the Antarctic sea sponge, Isodictya erinacea. The bioactivity of Ereb was investigated, and it was found to inhibit molting when fed to the arthropod species Orchomene plebs. Xanthurenic acid (XA) is a known endogenous molt regulator present in arthropods. Experimental stud...

Enzyme activity is inherently linked to free energies of transition states, ligand binding, protonation/deprotonation, etc.; these free energies, and thus enzyme function, can be affected by residue mutations, allosterically induced conformational changes, and much more. Therefore, being able to predict free energies associated with enzymatic proce...

Background: A homologue of the ecdysone receptor has previously been identified in human filarial parasites. As the ecdysone receptor is not found in vertebrates, it and the regulatory pathways it controls represent attractive potential chemotherapeutic targets. Methodology/ principal findings: Administration of 20-hydroxyecdysone to gerbils inf...

Strategy for production of a stable mammalian cell line for screening for agonists and antagonists of the BmaEcR. ‘X” = Gateway recombination cloning. Colored circles schematically indicate the specific sequences used in the Gateway recombination cloning reactions. (TIF)

MD simulation results. A) RMSD plotted over the course of 65 ns simulation, B) radius of gyration plotted over the course of 65 ns simulation, C) total energy of the homology model and ponasterone A complex monitored over the course of 65 ns simulation, and D) RMSF analysis for each residue in the EcR LBD homology model. (TIF)

Summary of RMSFs calculated from the MD simulation of for all residues within 3 Å of the 20-hydroxyecdysone binding site. Residue name is given on the left of each column and the RMSF is given to on the right. Residues are ordered by their residue number. Residues constituting the “hydrophobic pocket” are underlined. (DOCX)

Compounds identified by the in-silico virtual screening and their docking scores. (DOCX)

Homology modeling and virtual screening studies. (DOCX)

Ramachandaran plot compiled of the phi-psi backbone dihedrals from the model after molecular dynamics simulations. The legend illustrates the color designations of certain regions in the plot. The sum of the first two percentages indicates the number of residues in more favored regions (98.7%). (TIF)

Comparison of the transient transfection assay when conducted with NIH3T3 and HEK293 cells. (DOCX)

Superposition of Prime homology model (yellow) over I-Tasser homology model (blue). (TIF)

Summary of XP energy decomposition analyses. (DOCX)

Molting of L3 stage larvae when treated with 20-hydroxyecdysone. (DOCX)

Predicted structures of compounds docked in the active site of the BmaEcR LBD. Panel A: Compound 37. Panel B: Compound 38. Panel C: Compound 18. Panel D: Compound 36. (TIF)

Ferrochelatase catalyzes the insertion of ferrous iron into protoporphyrin IX to generate heme. Despite recent research on the reaction mechanism of ferrochelatase, the precise roles and localization of individual active site residues in catalysis, particularly those involved in the insertion of the ferrous iron into the protoporphyrin IX substrate...

Background: Accurately modeling condensed phase processes is one of computation's most difficult challenges. Include the possibility that conformational dynamics may be coupled to chemical reactions, where multiscale (i.e., QM/MM) methods are needed, and this task becomes even more daunting. Methods: Free energy simulations (i.e., molecular dyna...