Probing the Paclitaxel-microtubule Binding Site and Interactions: Design, Synthesis and Evaluation of New Photoaffinity Taxoids

2000 ◽  
Author(s):  
Jared Spletstoser ◽  
Gunda I. Georg
Keyword(s):  
Binding Site ◽  
Design Synthesis ◽  
Microtubule Binding

scholarly journals A Non-Motor Microtubule Binding Site Is Essential for the High Processivity and Mitotic Function of Kinesin-8 Kif18A

PLoS ONE ◽  
2011 ◽  
Vol 6 (11) ◽  
pp. e27471 ◽  
Author(s):  
Monika I. Mayr ◽  
Marko Storch ◽  
Jonathon Howard ◽  
Thomas U. Mayer
Keyword(s):  
Binding Site ◽  
Microtubule Binding

scholarly journals Design, Synthesis and Molecular Modeling Study of Conjugates of ADP and Morpholino Nucleosides as A Novel Class of Inhibitors of PARP-1, PARP-2 and PARP-3

2019 ◽  
Vol 21 (1) ◽  
pp. 214
Author(s):  
Yuliya V. Sherstyuk ◽  
Nikita V. Ivanisenko ◽  
Alexandra L. Zakharenko ◽  
Maria V. Sukhanova ◽  
Roman Y. Peshkov ◽  
...  
Keyword(s):  
Molecular Modeling ◽  
Binding Site ◽  
Rational Design ◽  
In Silico Analysis ◽  
Parp Inhibition ◽  
High Yield ◽  
Design Synthesis ◽  
Molecular Modeling Study ◽  
Parp 1 ◽  
Modeling Study

We report on the design, synthesis and molecular modeling study of conjugates of adenosine diphosphate (ADP) and morpholino nucleosides as potential selective inhibitors of poly(ADP-ribose)polymerases-1, 2 and 3. Sixteen dinucleoside pyrophosphates containing natural heterocyclic bases as well as 5-haloganeted pyrimidines, and mimicking a main substrate of these enzymes, nicotinamide adenine dinucleotide (NAD+)-molecule, have been synthesized in a high yield. Morpholino nucleosides have been tethered to the β-phosphate of ADP via a phosphoester or phosphoramide bond. Screening of the inhibiting properties of these derivatives on the autopoly(ADP-ribosyl)ation of PARP-1 and PARP-2 has shown that the effect depends upon the type of nucleobase as well as on the linkage between ADP and morpholino nucleoside. The 5-iodination of uracil and the introduction of the P–N bond in NAD+-mimetics have shown to increase inhibition properties. Structural modeling suggested that the P–N bond can stabilize the pyrophosphate group in active conformation due to the formation of an intramolecular hydrogen bond. The most active NAD+ analog against PARP-1 contained 5-iodouracil 2ʹ-aminomethylmorpholino nucleoside with IC50 126 ± 6 μM, while in the case of PARP-2 it was adenine 2ʹ-aminomethylmorpholino nucleoside (IC50 63 ± 10 μM). In silico analysis revealed that thymine and uracil-based NAD+ analogs were recognized as the NAD+-analog that targets the nicotinamide binding site. On the contrary, the adenine 2ʹ-aminomethylmorpholino nucleoside-based NAD+ analogs were predicted to identify as PAR-analogs that target the acceptor binding site of PARP-2, representing a novel molecular mechanism for selective PARP inhibition. This discovery opens a new avenue for the rational design of PARP-1/2 specific inhibitors.

Methods for Studying Microtubule Binding Site Interactions

2013 ◽  
pp. 303-325 ◽  
Author(s):  
Jessica J. Field ◽  
Enrique Calvo ◽  
Peter T. Northcote ◽  
John H. Miller ◽  
Karl-Heinz Altmann ◽  
...  
Keyword(s):  
Binding Site ◽  
Microtubule Binding

scholarly journals NSC 622124 Inhibits Human Eg5 and Other Kinesins via Interaction with the Conserved Microtubule-Binding Site†

Biochemistry ◽  
2009 ◽  
Vol 48 (8) ◽  
pp. 1754-1762 ◽  
Author(s):  
Sarah S. Learman ◽  
Catherine D. Kim ◽  
Nathaniel S. Stevens ◽  
Sunyoung Kim ◽  
Edward J. Wojcik ◽  
...  
Keyword(s):  
Binding Site ◽  
Microtubule Binding

scholarly journals Unravelling the Structure of the Tetrahedral Metal-Binding Site in METP3 through an Experimental and Computational Approach

Molecules ◽  
2021 ◽  
Vol 26 (17) ◽  
pp. 5221
Author(s):  
Salvatore La Gatta ◽  
Linda Leone ◽  
Ornella Maglio ◽  
Maria De Fenza ◽  
Flavia Nastri ◽  
...  
Keyword(s):  
Metal Ions ◽  
Binding Site ◽  
Metal Binding ◽  
Binding Sites ◽  
Metal Ion ◽  
Structural Determinants ◽  
Binding Properties ◽  
Tetrahedral Geometry ◽  
Design Synthesis ◽  
Metal Binding Sites

Understanding the structural determinants for metal ion coordination in metalloproteins is a fundamental issue for designing metal binding sites with predetermined geometry and activity. In order to achieve this, we report in this paper the design, synthesis and metal binding properties of METP3, a homodimer made up of a small peptide, which self assembles in the presence of tetrahedrally coordinating metal ions. METP3 was obtained through a redesign approach, starting from the previously developed METP molecule. The undecapeptide sequence of METP, which dimerizes to house a Cys4 tetrahedral binding site, was redesigned in order to accommodate a Cys2His2 site. The binding properties of METP3 were determined toward different metal ions. Successful assembly of METP3 with Co(II), Zn(II) and Cd(II), in the expected 2:1 stoichiometry and tetrahedral geometry was proven by UV-visible spectroscopy. CD measurements on both the free and metal-bound forms revealed that the metal coordination drives the peptide chain to fold into a turned conformation. Finally, NMR data of the Zn(II)-METP3 complex, together with a retrostructural analysis of the Cys-X-X-His motif in metalloproteins, allowed us to define the model structure. All the results establish the suitability of the short METP sequence for accommodating tetrahedral metal binding sites, regardless of the first coordination ligands.

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