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  1. Article ; Online: A member of the OSCA/TMEM63 family of mechanosensitive calcium channels participates in cell wall integrity maintenance in Aspergillus nidulans.

    Hill, Terry W / Vance, Stanley / Loome, Jennifer F / Haugen, Benard J / Loprete, Darlene M / Stoddard, Shana V / Jackson-Hayes, Loretta

    Fungal genetics and biology : FG & B

    2023  Volume 169, Page(s) 103842

    Abstract: The calF7 mutation in Aspergillus nidulans causes hypersensitivity to the cell wall compromising agents Calcofluor White (CFW) and Congo Red. In this research we demonstrate that the calF7 mutation resides in gene AN2880, encoding a predicted member of ... ...

    Abstract The calF7 mutation in Aspergillus nidulans causes hypersensitivity to the cell wall compromising agents Calcofluor White (CFW) and Congo Red. In this research we demonstrate that the calF7 mutation resides in gene AN2880, encoding a predicted member of the OSCA/TMEM63 family of transmembrane glycoproteins. Those members of the family whose physiological functions have been investigated have been shown to act as mechanosensitive calcium transport channels. Deletion of AN2880 replicates the CFW hypersensitivity phenotype. Separately, we show that CFW hypersensitivity of calF deletion strains can be overcome by inclusion of elevated levels of extracellular calcium ions in the growth medium, and, correspondingly, wild type strains grown in media deficient in calcium ions are no longer resistant to CFW. These observations support a model in which accommodation to at least some forms of cell wall stress is mediated by a calcium ion signaling system in which the AN2880 gene product plays a role. The genetic lesion in calF7 is predicted to result in a glycine-to-arginine substitution at position 638 of the 945-residue CalF protein in a region of the RSN1_7TM domain that is highly conserved amongst filamentous fungi. Homology modeling predicts that the consequence of a G638R substitution is to structurally occlude the principal conductance pore in the protein. GFP-tagged wild type CalF localizes principally to the Spitzenkörper and the plasma membrane at growing tips and forming septa. However, both septation and hyphal morphology appear to be normal in calF7 and AN2880 deletion strains, indicating that any role played by CalF in normal hyphal growth and cytokinesis is dispensable.
    MeSH term(s) Calcium Channels/metabolism ; Aspergillus nidulans/metabolism ; Calcium/metabolism ; Cell Wall/genetics ; Cell Wall/metabolism ; Ions/metabolism ; Fungal Proteins/metabolism
    Chemical Substances Calcium Channels ; Calcium (SY7Q814VUP) ; Ions ; Fungal Proteins
    Language English
    Publishing date 2023-10-05
    Publishing country United States
    Document type Journal Article
    ZDB-ID 1319820-8
    ISSN 1096-0937 ; 1087-1845 ; 0147-5975
    ISSN (online) 1096-0937
    ISSN 1087-1845 ; 0147-5975
    DOI 10.1016/j.fgb.2023.103842
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  2. Article ; Online: In silico

    V Stoddard, Shana / Dodson, Kyra / Adams, Kamesha / L Watkins, Davita

    International journal of molecular sciences

    2019  Volume 21, Issue 1

    Abstract: Histone deacetylases (HDAC) are being targeted for a number of diseases such as cancer, inflammatory disease, and neurological disorders. Within this family of 18 isozymes, HDAC4 is a prime target for glioma, one of the most aggressive brain tumors ... ...

    Abstract Histone deacetylases (HDAC) are being targeted for a number of diseases such as cancer, inflammatory disease, and neurological disorders. Within this family of 18 isozymes, HDAC4 is a prime target for glioma, one of the most aggressive brain tumors reported. Thus, the development of HDAC4 inhibitors could present a novel therapeutic route for glioma. In this work, molecular docking studies on cyclopropane hydroxamic acid derivatives identified five novel molecular interactions to the HDAC4 receptor that could be harnessed to enhance inhibitor binding. Thus, design guidelines for the optimization of potent HDAC4 inhibitors were developed which can be utilized to further the development of HDAC4 inhibitors. Using the developed guidelines, eleven novel cyclopropane hydroxamic acid derivatives were designed that outcompeted all original cyclopropane hydroxamic acids HDAC4 inhibitors studied
    MeSH term(s) Binding Sites ; Drug Design ; Histone Deacetylase Inhibitors/chemistry ; Histone Deacetylase Inhibitors/pharmacology ; Histone Deacetylases/chemistry ; Histone Deacetylases/metabolism ; Humans ; Molecular Docking Simulation/methods ; Protein Binding ; Repressor Proteins/antagonists & inhibitors ; Repressor Proteins/chemistry ; Repressor Proteins/metabolism
    Chemical Substances Histone Deacetylase Inhibitors ; Repressor Proteins ; HDAC4 protein, human (EC 3.5.1.98) ; Histone Deacetylases (EC 3.5.1.98)
    Language English
    Publishing date 2019-12-28
    Publishing country Switzerland
    Document type Journal Article
    ZDB-ID 2019364-6
    ISSN 1422-0067 ; 1422-0067 ; 1661-6596
    ISSN (online) 1422-0067
    ISSN 1422-0067 ; 1661-6596
    DOI 10.3390/ijms21010219
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  3. Article: Design and synthesis of diazine-based panobinostat analogues for HDAC8 inhibition.

    Balasubramaniam, Sivaraman / Vijayan, Sajith / Goldman, Liam V / May, Xavier A / Dodson, Kyra / Adhikari, Sweta / Rivas, Fatima / Watkins, Davita L / Stoddard, Shana V

    Beilstein journal of organic chemistry

    2020  Volume 16, Page(s) 628–637

    Abstract: Guided by computational analysis, herein we report the design, synthesis and evaluation of four novel diazine-based histone deacetylase inhibitors (HDACis). The targets of interest (TOI) are analogues of panobinostat, one of the most potent and versatile ...

    Abstract Guided by computational analysis, herein we report the design, synthesis and evaluation of four novel diazine-based histone deacetylase inhibitors (HDACis). The targets of interest (TOI) are analogues of panobinostat, one of the most potent and versatile HDACi reported. By simply replacing the phenyl core of panobinostat with that of a diazine derivative, docking studies against HDAC2 and HDAC8 revealed that the four analogues exhibit inhibition activities comparable to that of panobinostat. Multistep syntheses afforded the visualized targets
    Language English
    Publishing date 2020-04-07
    Publishing country Germany
    Document type Journal Article
    ZDB-ID 2192461-2
    ISSN 1860-5397
    ISSN 1860-5397
    DOI 10.3762/bjoc.16.59
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  4. Article ; Online: Structure and function insights garnered from in silico modeling of the thrombospondin type-1 domain-containing 7A antigen.

    Stoddard, Shana V / Welsh, Colin L / Palopoli, Maggie M / Stoddard, Serena D / Aramandla, Mounika P / Patel, Riya M / Ma, Hong / Beck, Laurence H

    Proteins

    2018  Volume 87, Issue 2, Page(s) 136–145

    Abstract: The thrombospondin type-1 domain containing 7A (THSD7A) protein is known to be one of the antigens responsible for the autoimmune disorder idiopathic membranous nephropathy. The structure of this antigen is currently unsolved experimentally. Here we ... ...

    Abstract The thrombospondin type-1 domain containing 7A (THSD7A) protein is known to be one of the antigens responsible for the autoimmune disorder idiopathic membranous nephropathy. The structure of this antigen is currently unsolved experimentally. Here we present a homology model of the extracellular portion of the THSD7A antigen. The structure was evaluated for folding patterns, epitope site prediction, and function was predicted. Results show that this protein contains 21 extracellular domains and with the exception of the first two domains, has a regular repeating pattern of TSP-1-like followed by F-spondin-like domains. Our results indicate the presence of a novel Trp-ladder sequence of WxxxxW in the TSP-1-like domains. Of the 21 domains, 18 were shown to have epitope binding sites as predicted by epitopia. Several of the F-spondin-like domains have insertions in the canonical TSP fold, most notably the coiled coil region in domain 4, which may be utilized in protein-protein binding interactions, suggesting that this protein functions as a heparan sulfate binding site.
    MeSH term(s) Amino Acid Sequence ; Binding Sites/genetics ; Computer Simulation ; Epitopes/chemistry ; Epitopes/genetics ; Epitopes/metabolism ; Glomerulonephritis, Membranous/genetics ; Glomerulonephritis, Membranous/metabolism ; Humans ; Models, Molecular ; Protein Domains ; Sequence Homology, Amino Acid ; Thrombospondins/chemistry ; Thrombospondins/genetics ; Thrombospondins/metabolism
    Chemical Substances Epitopes ; THSD7A protein, human ; Thrombospondins
    Language English
    Publishing date 2018-12-21
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ZDB-ID 806683-8
    ISSN 1097-0134 ; 0887-3585
    ISSN (online) 1097-0134
    ISSN 0887-3585
    DOI 10.1002/prot.25640
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  5. Article ; Online: Insights and ideas garnered from marine metabolites for development of dual-function acetylcholinesterase and amyloid-β aggregation inhibitors.

    Stoddard, Shana V / Hamann, Mark T / Wadkins, Randy M

    Marine drugs

    2014  Volume 12, Issue 4, Page(s) 2114–2131

    Abstract: Due to the diversity of biological activities that can be found in aquatic ecosystems, marine metabolites have been an active area of drug discovery for the last 30 years. Marine metabolites have been found to inhibit a number of enzymes important in the ...

    Abstract Due to the diversity of biological activities that can be found in aquatic ecosystems, marine metabolites have been an active area of drug discovery for the last 30 years. Marine metabolites have been found to inhibit a number of enzymes important in the treatment of human disease. Here, we focus on marine metabolites that inhibit the enzyme acetylcholinesterase, which is the cellular target for treatment of early-stage Alzheimer's disease. Currently, development of anticholinesterase drugs with improved potency, and drugs that act as dual acetylcholinesterase and amyloid-β aggregation inhibitors, are being sought to treat Alzheimer's disease. Seven classes of marine metabolites are reported to possess anti-cholinesterase activity. We compared these metabolites to clinically-used acetylcholinesterase inhibitors having known mechanisms of inhibition. We performed a docking simulation and compared them to published experimental data for each metabolite to determine the most likely mechanism of inhibition for each class of marine inhibitor. Our results indicate that several marine metabolites bind to regions of the acetylcholinesterase active site that are not bound by the clinically-used drugs rivastigmine, galanthamine, donepezil, or tacrine. We use the novel poses adopted for computational drug design of tighter binding anticholinesterase drugs likely to act as inhibitors of both acetylcholinesterase activity and amyloid-β aggregation inhibition.
    MeSH term(s) Acetylcholinesterase/drug effects ; Acetylcholinesterase/metabolism ; Alzheimer Disease/drug therapy ; Alzheimer Disease/physiopathology ; Amyloid beta-Peptides/antagonists & inhibitors ; Animals ; Aquatic Organisms/metabolism ; Binding Sites ; Cholinesterase Inhibitors/pharmacology ; Computer-Aided Design ; Drug Design ; Drug Discovery ; Humans ; Molecular Docking Simulation
    Chemical Substances Amyloid beta-Peptides ; Cholinesterase Inhibitors ; Acetylcholinesterase (EC 3.1.1.7)
    Keywords covid19
    Language English
    Publishing date 2014-04-04
    Publishing country Switzerland
    Document type Comparative Study ; Journal Article ; Research Support, N.I.H., Extramural ; Research Support, U.S. Gov't, Non-P.H.S.
    ZDB-ID 2175190-0
    ISSN 1660-3397 ; 1660-3397
    ISSN (online) 1660-3397
    ISSN 1660-3397
    DOI 10.3390/md12042114
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  6. Article ; Online: Design and synthesis of diazine-based panobinostat analogues for HDAC8 inhibition

    Sivaraman Balasubramaniam / Sajith Vijayan / Liam V. Goldman / Xavier A. May / Kyra Dodson / Sweta Adhikari / Fatima Rivas / Davita L. Watkins / Shana V. Stoddard

    Beilstein Journal of Organic Chemistry, Vol 16, Iss 1, Pp 628-

    2020  Volume 637

    Abstract: Guided by computational analysis, herein we report the design, synthesis and evaluation of four novel diazine-based histone deacetylase inhibitors (HDACis). The targets of interest (TOI) are analogues of panobinostat, one of the most potent and versatile ...

    Abstract Guided by computational analysis, herein we report the design, synthesis and evaluation of four novel diazine-based histone deacetylase inhibitors (HDACis). The targets of interest (TOI) are analogues of panobinostat, one of the most potent and versatile HDACi reported. By simply replacing the phenyl core of panobinostat with that of a diazine derivative, docking studies against HDAC2 and HDAC8 revealed that the four analogues exhibit inhibition activities comparable to that of panobinostat. Multistep syntheses afforded the visualized targets TOI1, TOI2, TOI3-rev and TOI4 whose biological evaluation confirmed the strength of HDAC8 inhibition with TOI4 displaying the greatest efficacy at varying concentrations. The results of this study lay the foundation for future design strategies toward more potent HDACis for HDAC8 isozymes and further therapeutic applications for neuroblastoma.
    Keywords diazine ; histone deacetylase ; inhibitors ; isozymes ; panobinostat ; Science ; Q ; Organic chemistry ; QD241-441
    Subject code 540
    Language English
    Publishing date 2020-04-01T00:00:00Z
    Publisher Beilstein-Institut
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  7. Article ; Online: Optimization Rules for SARS-CoV-2 M

    Stoddard, Shana V / Stoddard, Serena D / Oelkers, Benjamin K / Fitts, Kennedi / Whalum, Kellen / Whalum, Kaylah / Hemphill, Alexander D / Manikonda, Jithin / Martinez, Linda Michelle / Riley, Elizabeth G / Roof, Caroline M / Sarwar, Nowreen / Thomas, Doni M / Ulmer, Emily / Wallace, Felissa E / Pandey, Pankaj / Roy, Sudeshna

    Viruses

    2020  Volume 12, Issue 9

    Abstract: Coronaviruses are viral infections that have a significant ability to impact human health. Coronaviruses have produced two pandemics and one epidemic in the last two decades. The current pandemic has created a worldwide catastrophe threatening the lives ... ...

    Abstract Coronaviruses are viral infections that have a significant ability to impact human health. Coronaviruses have produced two pandemics and one epidemic in the last two decades. The current pandemic has created a worldwide catastrophe threatening the lives of over 15 million as of July 2020. Current research efforts have been focused on producing a vaccine or repurposing current drug compounds to develop a therapeutic. There is, however, a need to study the active site preferences of relevant targets, such as the SARS-CoV-2 main protease (SARS-CoV-2 M
    MeSH term(s) Antiviral Agents/chemistry ; Antiviral Agents/pharmacology ; Betacoronavirus/drug effects ; Betacoronavirus/enzymology ; Binding Sites ; COVID-19 ; Catalytic Domain ; Coronavirus 3C Proteases ; Coronavirus Infections/drug therapy ; Coronavirus Infections/virology ; Cysteine Endopeptidases/chemistry ; Cysteine Endopeptidases/metabolism ; Drug Design ; Drug Repositioning ; Humans ; Molecular Docking Simulation/methods ; Molecular Dynamics Simulation ; Pandemics ; Pneumonia, Viral/drug therapy ; Pneumonia, Viral/virology ; Protease Inhibitors/chemistry ; Protease Inhibitors/pharmacology ; Protein Conformation ; SARS-CoV-2 ; Viral Nonstructural Proteins/chemistry ; Viral Nonstructural Proteins/metabolism
    Chemical Substances Antiviral Agents ; Protease Inhibitors ; Viral Nonstructural Proteins ; Cysteine Endopeptidases (EC 3.4.22.-) ; Coronavirus 3C Proteases (EC 3.4.22.28)
    Keywords covid19
    Language English
    Publishing date 2020-08-26
    Publishing country Switzerland
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 2516098-9
    ISSN 1999-4915 ; 1999-4915
    ISSN (online) 1999-4915
    ISSN 1999-4915
    DOI 10.3390/v12090942
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  8. Article ; Online: Design of Potent Panobinostat Histone Deacetylase Inhibitor Derivatives: Molecular Considerations for Enhanced Isozyme Selectivity between HDAC2 and HDAC8.

    Stoddard, Shana V / May, Xavier A / Rivas, Fatima / Dodson, Kyra / Vijayan, Sajith / Adhika, Swetha / Parker, Kordarius / Watkins, Davita L

    Molecular informatics

    2018  Volume 38, Issue 3, Page(s) e1800080

    Abstract: Histone Deacetylases (HDACs) are an important family of 18 isozymes, which are being pursued as drug targets for many types of disorders. HDAC2 and HDAC8 are two of the isozymes, which have been identified as drug targets for the design of anti-cancer, ... ...

    Abstract Histone Deacetylases (HDACs) are an important family of 18 isozymes, which are being pursued as drug targets for many types of disorders. HDAC2 and HDAC8 are two of the isozymes, which have been identified as drug targets for the design of anti-cancer, neurodegenerative, immunological, and anti-parasitic agents. Design of potent HDAC2 and HDAC8 inhibitors will be useful for the therapeutic advances in many disorders. This work was undertaken to develop potent HDAC2 and HDAC8 inhibitors. A docking study was performed comparing panobinostat derivatives in both HDAC2 and HDAC8. Six of our derivatives showed stronger binding to HDAC2 than panobinostat, and two of our derivatives showed stronger binding to HDAC8 than panobinostat. We evaluated the molecular features, which improved potency of our inhibitors over panobinostat and also identified another molecular consideration, which could be used to enhance histone deacetylase inhibitor (HDACi) selectivity towards either the HDAC2 or HDAC8 isozymes. The results of this work can be used to assist future design of more potent and selective HDACi for HDAC2 and HDAC8.
    MeSH term(s) Binding Sites ; Drug Design ; Histone Deacetylase 2/chemistry ; Histone Deacetylase 2/metabolism ; Histone Deacetylase Inhibitors/chemistry ; Histone Deacetylase Inhibitors/pharmacology ; Histone Deacetylases/chemistry ; Histone Deacetylases/metabolism ; Humans ; Molecular Docking Simulation ; Panobinostat/analogs & derivatives ; Protein Binding ; Repressor Proteins/chemistry ; Repressor Proteins/metabolism ; Substrate Specificity
    Chemical Substances Histone Deacetylase Inhibitors ; Repressor Proteins ; Panobinostat (9647FM7Y3Z) ; HDAC2 protein, human (EC 3.5.1.98) ; HDAC8 protein, human (EC 3.5.1.98) ; Histone Deacetylase 2 (EC 3.5.1.98) ; Histone Deacetylases (EC 3.5.1.98)
    Language English
    Publishing date 2018-10-22
    Publishing country Germany
    Document type Journal Article ; Research Support, Non-U.S. Gov't ; Research Support, U.S. Gov't, Non-P.H.S.
    ZDB-ID 2537668-8
    ISSN 1868-1751 ; 1868-1743
    ISSN (online) 1868-1751
    ISSN 1868-1743
    DOI 10.1002/minf.201800080
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  9. Article: In Silico Design and Evaluation of Carboxylesterase Inhibitors.

    Stoddard, Shana V / Yu, Xiaozhen / Potter, Philip M / Wadkins, Randy M

    Journal of pest science

    2013  Volume 35, Issue 3, Page(s) 240–249

    Abstract: Carboxylesterases (CEs) are important enzymes that catalyze biological detoxification, hydrolysis of certain pesticides, and metabolism of many esterified drugs. The development of inhibitors for CE has many potential uses, including increasing drug ... ...

    Abstract Carboxylesterases (CEs) are important enzymes that catalyze biological detoxification, hydrolysis of certain pesticides, and metabolism of many esterified drugs. The development of inhibitors for CE has many potential uses, including increasing drug lifetime and altering biodistrubution; reducing or abrogating toxicity of metabolized drugs; and reducing pest resistance to insecticides. In this review, we discuss the major classes of known mammalian CE inhibitors and describe our computational efforts to design new scaffolds for development of novel, selective inhibitors. We discuss several strategies for
    Language English
    Publishing date 2013-03-13
    Publishing country Germany
    Document type Journal Article
    ZDB-ID 2141662-X
    ISSN 1612-4766 ; 1439-0280 ; 1612-4758
    ISSN (online) 1612-4766 ; 1439-0280
    ISSN 1612-4758
    DOI 10.1584/jpestics.R10-06
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  10. Article ; Online: Insights and Ideas Garnered from Marine Metabolites for Development of Dual-Function Acetylcholinesterase and Amyloid-β Aggregation Inhibitors

    Shana V. Stoddard / Mark T. Hamann / Randy M. Wadkins

    Marine Drugs, Vol 12, Iss 4, Pp 2114-

    2014  Volume 2131

    Abstract: Due to the diversity of biological activities that can be found in aquatic ecosystems, marine metabolites have been an active area of drug discovery for the last 30 years. Marine metabolites have been found to inhibit a number of enzymes important in the ...

    Abstract Due to the diversity of biological activities that can be found in aquatic ecosystems, marine metabolites have been an active area of drug discovery for the last 30 years. Marine metabolites have been found to inhibit a number of enzymes important in the treatment of human disease. Here, we focus on marine metabolites that inhibit the enzyme acetylcholinesterase, which is the cellular target for treatment of early-stage Alzheimer’s disease. Currently, development of anticholinesterase drugs with improved potency, and drugs that act as dual acetylcholinesterase and amyloid-β aggregation inhibitors, are being sought to treat Alzheimer’s disease. Seven classes of marine metabolites are reported to possess anti-cholinesterase activity. We compared these metabolites to clinically-used acetylcholinesterase inhibitors having known mechanisms of inhibition. We performed a docking simulation and compared them to published experimental data for each metabolite to determine the most likely mechanism of inhibition for each class of marine inhibitor. Our results indicate that several marine metabolites bind to regions of the acetylcholinesterase active site that are not bound by the clinically-used drugs rivastigmine, galanthamine, donepezil, or tacrine. We use the novel poses adopted for computational drug design of tighter binding anticholinesterase drugs likely to act as inhibitors of both acetylcholinesterase activity and amyloid-β aggregation inhibition.
    Keywords molecular docking ; enzyme inhibitor ; sesquiterpene acetate ; pyrrole ; tetrazacyclopentazulene ; bromotyrosine derivative ; plastoquinone ; farnesylacetone ; Biology (General) ; QH301-705.5
    Subject code 500
    Language English
    Publishing date 2014-04-01T00:00:00Z
    Publisher MDPI AG
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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