scholarly journals New Ligands and New Insights for Vitamin D Receptor from Charge Density

2014 ◽  
Vol 70 (a1) ◽  
pp. C966-C966
Author(s):  
Maura Malińska ◽  
Andrzej Kutner ◽  
Krzysztof Woźniak
Keyword(s):  
Vitamin D ◽  
Hydrogen Bonds ◽  
Charge Density ◽  
Interaction Energy ◽  
Vitamin D Receptor ◽  
Electrostatic Interaction ◽  
Interaction Energies ◽  
Average Strength ◽  
Vitamin D Analogs ◽  
Wide Range

Vitamin D protective effects result from its role as a nuclear transcription factor that regulates cell growth, differentiation, and a wide range of cellular mechanisms crucial to the development and progression of cancer.[1] Many academic investigators and pharmaceutical companies try to develop calcitriol analogs that exhibit equal or even increased anti-proliferative activity while exhibiting a reduced tendency to cause hypercalcemia. Analysis of 24 Vitamin D analogs bearing similar molecular structures with a complex of a Vitamin D Receptor (VDR) enabled the design of new agonists (TB1, TB2, TB3 and TB4). Undertaken approach was to minimize the electrostatic interaction energies available after the reconstruction of charge density with the aid of the pseudoatom databank (UBDB[2]). Comprehensive studies revealed 29 residues crucial for agonist binding. Trp286, which is specific to VDR among the representatives of the Nuclear Receptor Family, plays the crucial role of positioning the ligand forming dispersive interactions, mostly C-H...π, with an average strength of -4 kcal mol-1. The ligand binding pocket is primarily composed of hydrophobic residues, however there are 6 hydrogen bonds characteristic for all the ligands. They electrostatic interaction energies strongly contribute to the total interaction energy, with an average strength of -8, -19, -11 and -12 kcal mol-1 for hydrogen bonds to Ser237, Arg274, Ser278 and Tyr143. The aliphatic chain of the Vitamin D analogs adopt an extended conformation and the 25-hydroxyl group is hydrogen bonded to His305 and His397 with electrostatic interaction energies of -13 and -11 kcal mol-1. The geometries of complexes of the proposed ligand with VDR were obtained by the docking procedure implemented in Autodock4.3[3]. New agonsits form all mentioned before interactions with VDR. The final results of electrostatic interaction energy for TB1 and TB2 are -153 and -120 kcal mol-1, and this results are the smallest among all studied Vitamin D analogs.

Molecular tapes in the structure of isoguaninium chloride

2017 ◽  
Vol 74 (1) ◽  
pp. 108-112 ◽  
Author(s):  
Urszula Anna Budniak ◽  
Paulina Maria Dominiak
Keyword(s):  
Crystal Structure ◽  
Single Crystal ◽  
Charge Density ◽  
Interaction Energy ◽  
Electrostatic Interaction ◽  
Electrostatic Interactions ◽  
The Other ◽  
X Ray Diffraction ◽  
X Ray ◽  
Diffraction Structure

Isoguanine, an analogue of guanine, is of intrinsic interest as a noncanonical nucleobase. The crystal structure of isoguaninium chloride (systematic name: 6-amino-2-oxo-1H,7H-purin-3-ium chloride), C5H6N5O+·Cl−, has been determined by single-crystal X-ray diffraction. Structure analysis was supported by electrostatic interaction energy (E es) calculations based on charge density reconstructed with the UBDB databank. In the structure, two kinds of molecular tapes are observed, one parallel to (010) and the other parallel to (50\overline{4}). The tapes are formed by dimers of isoguaninium cations interacting with chloride anions. E es analysis indicates that cations in one kind of tape are oriented so as to minimize repulsive electrostatic interactions.

Fast analytical evaluation of intermolecular electrostatic interaction energies using the pseudoatom representation of the electron density. III. Application to crystal structures via the Ewald and direct summation methods

2020 ◽  
Vol 76 (6) ◽  
pp. 630-651
Author(s):  
Daniel Nguyen ◽  
Piero Macchi ◽  
Anatoliy Volkov
Keyword(s):  
Interaction Energy ◽  
Crystal Structures ◽  
Electron Density ◽  
Small Molecule ◽  
Electrostatic Interaction ◽  
Multipole Moment ◽  
Interaction Energies ◽  
Acta Cryst ◽  
Löwdin Α Function ◽  
Direct Summation

The previously reported exact potential and multipole moment (EP/MM) method for fast and accurate evaluation of the intermolecular electrostatic interaction energies using the pseudoatom representation of the electron density [Volkov, Koritsanszky & Coppens (2004). Chem. Phys. Lett. 391, 170–175; Nguyen, Kisiel & Volkov (2018). Acta Cryst. A74, 524–536; Nguyen & Volkov (2019). Acta Cryst. A75, 448–464] is extended to the calculation of electrostatic interaction energies in molecular crystals using two newly developed implementations: (i) the Ewald summation (ES), which includes interactions up to the hexadecapolar level and the EP correction to account for short-range electron-density penetration effects, and (ii) the enhanced EP/MM-based direct summation (DS), which at sufficiently large intermolecular separations replaces the atomic multipole moment approximation to the electrostatic energy with that based on the molecular multipole moments. As in the previous study [Nguyen, Kisiel & Volkov (2018). Acta Cryst. A74, 524–536], the EP electron repulsion integral is evaluated analytically using the Löwdin α-function approach. The resulting techniques, incorporated in the XDPROP module of the software package XD2016, have been tested on several small-molecule crystal systems (benzene, L-dopa, paracetamol, amino acids etc.) and the crystal structure of a 181-atom decapeptide molecule (Z = 4) using electron densities constructed via the University at Buffalo Aspherical Pseudoatom Databank [Volkov, Li, Koritsanszky & Coppens (2004). J. Phys. Chem. A, 108, 4283–4300]. Using a 2015 2.8 GHz Intel Xeon E3-1505M v5 computer processor, a 64-bit implementation of the Löwdin α-function and one of the higher optimization levels in the GNU Fortran compiler, the ES method evaluates the electrostatic interaction energy with a numerical precision of at least 10−5 kJ mol−1 in under 6 s for any of the tested small-molecule crystal structures, and in 48.5 s for the decapeptide structure. The DS approach is competitive in terms of precision and speed with the ES technique only for crystal structures of small molecules that do not carry a large molecular dipole moment. The electron-density penetration effects, correctly accounted for by the two described methods, contribute 28–64% to the total electrostatic interaction energy in the examined systems, and thus cannot be neglected.

scholarly journals Charge density studies of interactions in macromolecules – the case of sunitinib

2014 ◽  
Vol 70 (a1) ◽  
pp. C970-C970
Author(s):  
Maura Malińska ◽  
Katarzyna Jarzembska ◽  
Anna Goral ◽  
Andrzej Kutner ◽  
Krzysztof Woźniak ◽  
...  
Keyword(s):  
Charge Density ◽  
Interaction Energy ◽  
Electron Density ◽  
Electrostatic Interaction ◽  
Tyrosine Kinases ◽  
Electrostatic Interactions ◽  
Kinase Inhibitor ◽  
Topological Analysis ◽  
3D Structure ◽  
X Ray

Electron density is a key factor in determining properties of molecules. Knowledge of the electron density distribution allows to determine not only the 3D structure of molecules, but also various one-electron properties (electric moments, electrostatic potential, electrostatic interaction energy, etc.). X-ray diffraction is a great tool for obtaining this kind of information. For macromolecules, however, quantitative determination of charge density from experiment is possible on rare occasions only. We will present that with the University at Buffalo pseudoatom database (UBDB) approach [1,2] it is now possible to reconstruct electron density of any macromolecular system for which atomic coordinates are available. The approach is fast and opens an excellent opportunity to investigate macromolecular complexes by means of topological analysis of electron density (and derivatives thereof), electrostatic interaction energy analysis, and many others. The results of our studies on sunitinib (SU) will illustrate the possibilities of the approach. SU is an inhibitor of tyrosine kinases and was approved as a drug in 2006. Comprehensive analysis of the SU malate crystal and SU complexes with a series of protein kinases was carried out. The high resolution single crystal X-ray measurement and UBDB approach served as the basis for the reconstruction of the charge density of SU and the protein complexes. Hirshfeld surface and topological analyses revealed a similar interaction pattern in the SU malate crystal to that in the protein binding pockets. SU forms nine preserved bond paths corresponding to hydrogen bonds and also to the C-H...O and C-H...π contacts common for all analyzed kinases. It interacts typically with similar electrostatic interaction energy with the studied proteins and can adjust its conformation to fit the binding pocket in a way to enhance the electrostatic interactions. Such behavior can be responsible for a broad spectrum of action of SU as kinase inhibitor.

Altered Vitamin D receptor–coactivator interactions reflect superagonism of Vitamin D analogs

2005 ◽  
Vol 97 (1-2) ◽  
pp. 65-68 ◽  
Author(s):  
Guy Eelen ◽  
Lieve Verlinden ◽  
Mark Van Camp ◽  
Frank Claessens ◽  
Pierre De Clercq ◽  
...  
Keyword(s):  
Vitamin D ◽  
Vitamin D Receptor ◽  
Vitamin D Analogs

Crystal Structures of Rat Vitamin D Receptor Bound to Adamantyl Vitamin D Analogs: Structural Basis for Vitamin D Receptor Antagonism and Partial Agonism

2008 ◽  
Vol 51 (17) ◽  
pp. 5320-5329 ◽  
Author(s):  
Makoto Nakabayashi ◽  
Sachiko Yamada ◽  
Nobuko Yoshimoto ◽  
Takashi Tanaka ◽  
Miharu Igarashi ◽  
...  
Keyword(s):  
Vitamin D ◽  
Crystal Structures ◽  
Vitamin D Receptor ◽  
Structural Basis ◽  
Partial Agonism ◽  
Receptor Antagonism ◽  
Vitamin D Analogs

scholarly journals The genome-wide analysis of the vitamin D receptor binding sites evidences a wide range of potential therapeutic applications of vitamin D

2016 ◽  
Vol 1 (1) ◽  
pp. 12-21 ◽  
Author(s):  
O. A. Gromova ◽  
I. Y. Torshin ◽  
V. B. Spirichev
Keyword(s):  
Vitamin D ◽  
Vitamin D Receptor ◽  
Binding Sites ◽  
Bioinformatic Analysis ◽  
Genome Wide Analysis ◽  
Genome Wide ◽  
Wide Range ◽  
Receptor Interactions ◽  
The Impact ◽  
Fetal Stage

The article presents the results of the genome-wide bioinformatic analysis of the vitamin D receptor interactions with the human genome DNA. Using a biological system assay, biological roles of proteins were analyzed that are specifically associated with the impact of VDR receptor. Systematization of the biological roles of vitamin D opens broad and previously unexplored perspectives for pediatric applications of vitamin D preparations for the prevention and treatment of a wide range of diseases starting from the fetal stage and early childhood.

Development of Vitamin D Analogs Modulating the Pocket Structure of Vitamin D Receptor

2014 ◽  
Vol 14 (21) ◽  
pp. 2378-2387 ◽  
Author(s):  
Keiko Yamamoto ◽  
Yasuaki Anami ◽  
Toshimasa Itoh
Keyword(s):  
Vitamin D ◽  
Vitamin D Receptor ◽  
Vitamin D Analogs

scholarly journals Antiproliferative Activity of Non-Calcemic Vitamin D Analogs on Human Melanoma Lines in Relation to VDR and PDIA3 Receptors

2018 ◽  
Vol 19 (9) ◽  
pp. 2583 ◽  
Author(s):  
Tomasz Wasiewicz ◽  
Anna Piotrowska ◽  
Justyna Wierzbicka ◽  
Andrzej Slominski ◽  
Michal Zmijewski
Keyword(s):  
Vitamin D ◽  
Cell Lines ◽  
Vitamin D Receptor ◽  
Melanoma Cell ◽  
Human Melanoma ◽  
Side Chain ◽  
Short Side ◽  
Vitamin D Analogs ◽  
Splicing Variants ◽  
Melanoma Cell Lines

Vitamin D is a precursor for secosteroidal hormones, which demonstrate pleiotropic biological activities, including the regulation of growth and the differentiation of normal and malignant cells. Our previous studies have indicated that the inhibition of melanoma proliferation by a short side-chain, low calcemic analog of vitamin D—21(OH)pD is not fully dependent on the expression of vitamin D receptor (VDR). We have examined the effects of classic vitamin D metabolites, 1,25(OH)2D3 and 25(OH)D3, and two low calcemic vitamin D analogs, (21(OH)pD and calcipotriol), on proliferation, mRNA expression and vitamin D receptor (VDR) translocation in three human melanoma cell lines: WM98, A375 and SK-MEL-188b (subline b of SK-MEL-188, which lost responsiveness to 1,25(OH)2D3 and became VDR−/−CYP27B1−/−). All tested compounds efficiently inhibited the proliferation of WM98 and A375 melanoma cells except SK-MEL-188b, in which only the short side-chain vitamin D analog—21(OH)pD was effective. Overall, 21(OH)pD was the most potent compound in all three melanoma cell lines in the study. The lack of responsiveness of SK-MEL-188b to 1,25(OH)2D3, 25(OH)D3 and calcipotriol is explained by a lack of characteristic transcripts for the VDR, its splicing variants as well as for vitamin D-activating enzyme CYP27B1. On the other hand, the expression of VDR and its splicing variants and other vitamin D related genes (RXR, PDIA3, CYP3A4, CYP2R1, CYP27B1, CYP24A1 and CYP11A1) was detected in WM98 and A375 melanomas with the transcript levels being modulated by vitamin D analogs. The expression of VDR isoforms in WM98 cells was stimulated strongly by calcipotriol. The antiproliferative activities of 21(OH)pD appear not to require VDR translocation to the nucleus, which explains the high efficacy of this noncalcemic pregnacalciferol analog in SK-MEL-188b melanoma, that is, VDR−/−. Therefore, we propose that 21(OH)pD is a good candidate for melanoma therapy, although the mechanism of its action remains to be defined.

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