Elucidating the Dynamics and Selective Mechanistic Mode of Inhibition of a Novel Poly ADP-Ribose Polymerase-1 Inhibitor

2021 ◽  
Vol 18 ◽  
Author(s):  
Felix O. Okunlola ◽  
Opeyemi S. Soremekun ◽  
Fisayo A. Olotu ◽  
Mahmoud E. S. Soliman
Keyword(s):  
Focal Point ◽  
Computational Simulation ◽  
Selective Inhibition ◽  
Structural Flexibility ◽  
Halogen Bonds ◽  
Rational Structure ◽  
Inhibitor Binding ◽  
Dna Damage And Repair ◽  
Parp 1 ◽  
Ring Stability

: Poly ADP-ribose polymerase-1 (PARP-1), due to its role in DNA damage and repair, has been identified as a crucial therapeutic target to attenuate cancer development and progression. More so, selective inhibition has remained a focal point in PARP-1 targeting and has led to the development of numerous compounds, including the recently identified Cpd10n, a novel homoerythrina alkaloid derivative. To expound on the selective PARP-1 inhibition mechanisms by Cpd10n, we employed computational simulation methods in this study. Findings revealed that the inhibitor stabilized the characteristic motion of activated PARP-1 as evidenced by reductions in residual deviations and structural flexibility. Findings further revealed that Cpd10n was favorably bound at the active site PARP-1 as supported by the occurrence of strong hydrogen and halogen bonds based on complementarity. These were in addition to aromatic bonds with an enhanced ring to ring stability. Steady and high-affinity interactions between the fluorine atom of Cpd10n and Glu988 could potentiate the selective activity of the compound. Interaction analyses also revealed that inhibitor binding was strongly dependent on electrostatic effects over van der Waal contributions, which were relatively minimal. We believe findings from this study will further contribute to the rational structure-based design of highly selective PARP-1 inhibitors.

Effect of PARP-1 deficiency on DNA damage and repair in human bronchial epithelial cells exposed to Benzo(a)pyrene

2009 ◽  
Vol 36 (8) ◽  
pp. 2413-2422 ◽  
Author(s):  
Gong-hua Tao ◽  
Lin-qing Yang ◽  
Chun-mei Gong ◽  
Hai-yan Huang ◽  
Jian-dong Liu ◽  
...  
Keyword(s):  
Dna Damage ◽  
Epithelial Cells ◽  
Bronchial Epithelial Cells ◽  
Human Bronchial Epithelial Cells ◽  
Dna Damage And Repair ◽  
Bronchial Epithelial ◽  
Parp 1

scholarly journals Structural flexibility of halogen bonds showed in a single-crystal-to-single-crystal [2+2] photodimerization

IUCrJ ◽  
2018 ◽  
Vol 5 (4) ◽  
pp. 491-496 ◽  
Author(s):  
Michael A. Sinnwell ◽  
Jared N. Blad ◽  
Logan R. Thomas ◽  
Leonard R. MacGillivray
Keyword(s):  
Hydrogen Bonds ◽  
Single Crystal ◽  
Halogen Bonding ◽  
Solid State Reactions ◽  
Structural Flexibility ◽  
Halogen Bonds ◽  
Bonded Materials ◽  
Limited Opportunity ◽  
Structural Database ◽  
Geometric Changes

Halogen bonds have emerged as noncovalent forces that govern the assembly of molecules in organic solids with a degree of reliability akin to hydrogen bonds. Although the structure-directing roles of halogen bonds are often compared to hydrogen bonds, general knowledge concerning the fundamental structural behavior of halogen bonds has had limited opportunity to develop. Following an investigation of solid-state reactions involving organic syntheses and the development of photoresponsive materials, this work demonstrates the ability of the components of intermolecular N...I halogen bonding – a `workhorse' interaction for the crystal engineer – to support a single-crystal-to-single-crystal [2+2] photodimerization. A comparison is provided of the geometric changes experienced by the halogen-bonded components in the single-crystal reaction to the current crystal landscape of N...I halogen bonds, as derived from the Cambridge Structural Database. Specifically, a linear-to-bent type of deformation of the halogen-bonded components was observed, which is expected to support the development of functional halogen-bonded materials containing molecules that can undergo movements in close-packed crystal environments.

scholarly journals PARP-1: Friend or Foe of DNA Damage and Repair in Tumorigenesis?

Cancers ◽  
2013 ◽  
Vol 5 (4) ◽  
pp. 943-958 ◽  
Author(s):  
Amanda Swindall ◽  
Jennifer Stanley ◽  
Eddy Yang
Keyword(s):  
Dna Damage ◽  
Dna Damage And Repair ◽  
Parp 1

Perspective of structural flexibility on selective inhibition towards CYP1B1 over CYP1A1 by α-naphthoflavone analogs

2021 ◽  
Author(s):  
Ying Wang ◽  
Baichun Hu ◽  
Yupeng Zhang ◽  
Dong Wang ◽  
Zhaohu Luo ◽  
...  
Keyword(s):  
Protein Domains ◽  
Selective Inhibition ◽  
Structural Flexibility ◽  
Stacking Interactions ◽  
Π Stacking

The structural flexibility of protein domains mainly orchestrated the sustainability of crucial π–π stacking interactions with the key phenylalanine residues of CYP1A1 and CYP1B1, thereby determining the inhibitory selectivity towards CYP1B1.

Structural and functional characterization of an arylamineN-acetyltransferase from the pathogenMycobacterium abscessus: differences from other mycobacterial isoforms and implications for selective inhibition

2014 ◽  
Vol 70 (11) ◽  
pp. 3066-3079 ◽  
Author(s):  
Angélique Cocaign ◽  
Xavier Kubiak ◽  
Ximing Xu ◽  
Guillaume Garnier ◽  
Inès Li de la Sierra-Gallay ◽  
...  
Keyword(s):  
Functional Characterization ◽  
Selective Inhibition ◽  
Docking Studies ◽  
Chemotherapeutic Agents ◽  
Mycobacterium Abscessus ◽  
Inhibitor Binding ◽  
Functional Studies ◽  
Aromatic Substrates ◽  
Substrate Inhibitor

Mycobacterium abscessusis the most pathogenic rapid-growing mycobacterium and is one of the most resistant organisms to chemotherapeutic agents. However, structural and functional studies ofM. abscessusproteins that could modify/inactivate antibiotics remain nonexistent. Here, the structural and functional characterization of an arylamineN-acetyltransferase (NAT) fromM. abscessus[(MYCAB)NAT1] are reported. This novel prokaryotic NAT displays significantN-acetyltransferase activity towards aromatic substrates, including antibiotics such as isoniazid andp-aminosalicylate. The enzyme is endogenously expressed and functional in both the rough and smoothM. abscessusmorphotypes. The crystal structure of (MYCAB)NAT1 at 1.8 Å resolution reveals that it is more closely related toNocardia farcinicaNAT than to mycobacterial isoforms. In particular, structural and physicochemical differences from other mycobacterial NATs were found in the active site. Peculiarities of (MYCAB)NAT1 were further supported by kinetic and docking studies showing that the enzyme was poorly inhibited by the piperidinol inhibitor of mycobacterial NATs. This study describes the first structure of an antibiotic-modifying enzyme fromM. abscessusand provides bases to better understand the substrate/inhibitor-binding specificities among mycobacterial NATs and to identify/optimize specific inhibitors. These data should also contribute to the understanding of the mechanisms that are responsible for the pathogenicity and extensive chemotherapeutic resistance ofM. abscessus.

scholarly journals Targeting structural flexibility in HIV-1 protease inhibitor binding

2007 ◽  
Vol 12 (3-4) ◽  
pp. 132-138 ◽  
Author(s):  
Viktor Hornak ◽  
Carlos Simmerling
Keyword(s):  
Protease Inhibitor ◽  
Structural Flexibility ◽  
Inhibitor Binding ◽  
Hiv 1

scholarly journals Modulating carnitine levels by targeting its biosynthesis – selective inhibition of γ-butyrobetaine hydroxylase

2014 ◽  
Vol 5 (5) ◽  
pp. 1765-1771 ◽  
Author(s):  
Anna M. Rydzik ◽  
Rasheduzzaman Chowdhury ◽  
Grazyna T. Kochan ◽  
Sophie T. Williams ◽  
Michael A. McDonough ◽  
...  
Keyword(s):  
Conformational Changes ◽  
Selective Inhibition ◽  
Selective Inhibitors ◽  
Hydroxylase Activity ◽  
Inhibitor Binding

Potent and selective inhibitors of γ-butyrobetaine hydroxylase were developed. Conformational changes on inhibitor binding rationalise regulation of γ-butyrobetaine hydroxylase activity by high levels of γ-butyrobetaine.

Integrating perspectives: How the development of second-personal competence lays the foundation for a second-personal morality

2020 ◽  
Vol 43 ◽  
Author(s):  
John Corbit ◽  
Chris Moore
Keyword(s):  
Empirical Evidence ◽  
Developmental Process ◽  
Focal Point ◽  
Personal Information ◽  
Personal Competence ◽  
Triadic Interactions ◽  
Personal Morality ◽  
Integrative Process

Abstract The integration of first-, second-, and third-personal information within joint intentional collaboration provides the foundation for broad-based second-personal morality. We offer two additions to this framework: a description of the developmental process through which second-personal competence emerges from early triadic interactions, and empirical evidence that collaboration with a concrete goal may provide an essential focal point for this integrative process.

CBED Shadow Images and Cs:Aberration Measurement

1982 ◽  
Vol 40 ◽  
pp. 696-697
Author(s):  
R. W. Carpenter ◽  
I.Y.T. Chan ◽  
J. M. Cowley
Keyword(s):  
Focal Point ◽  
Spherical Aberration ◽  
Optic Axis ◽  
Wide Angle ◽  
Caustic Surface ◽  
Convergent Beam

Wide-angle convergent beam shadow images(CBSI) exhibit several characteristic distortions resulting from spherical aberration. The most prominent is a circle of infinite magnification resulting from rays having equal values of a forming a cross-over on the optic axis at some distance before reaching the paraxial focal point. This distortion is called the tangential circle of infinite magnification; it can be used to align and stigmate a STEM and to determine Cs for the probe forming lens. A second distortion, the radial circle of infinite magnification, results from a cross-over on the lens caustic surface of rays with differing values of ∝a, also before the paraxial focal point of the lens.

Electrostatic optics and aberration correction in the 1940s and today

1992 ◽  
Vol 50 (1) ◽  
pp. 6-7
Author(s):  
Gertrude F. Rempfer
Keyword(s):  
Electron Microscope ◽  
Focal Point ◽  
Focal Length ◽  
High Vacuum ◽  
Electron Optics ◽  
Applied Physics ◽  
Electrostatic Lenses ◽  
Commercial Instrument ◽  
The University ◽  
Theory And Experiment

I became involved in electron optics in early 1945, when my husband Robert and I were hired by the Farrand Optical Company. My husband had a mathematics Ph.D.; my degree was in physics. My main responsibilities were connected with the development of an electrostatic electron microscope. Fortunately, my thesis research on thermionic and field emission, in the late 1930s under the direction of Professor Joseph E. Henderson at the University of Washington, provided a foundation for dealing with electron beams, high vacuum, and high voltage.At the Farrand Company my co-workers and I used an electron-optical bench to carry out an extensive series of tests on three-electrode electrostatic lenses, as a function of geometrical and voltage parameters. Our studies enabled us to select optimum designs for the lenses in the electron microscope. We early on discovered that, in general, electron lenses are not “thin” lenses, and that aberrations of focal point and aberrations of focal length are not the same. I found electron optics to be an intriguing blend of theory and experiment. A laboratory version of the electron microscope was built and tested, and a report was given at the December 1947 EMSA meeting. The micrograph in fig. 1 is one of several which were presented at the meeting. This micrograph also appeared on the cover of the January 1949 issue of Journal of Applied Physics. These were exciting times in electron microscopy; it seemed that almost everything that happened was new. Our opportunities to publish were limited to patents because Mr. Farrand envisaged a commercial instrument. Regrettably, a commercial version of our laboratory microscope was not produced.

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