Atom-based and Pharmacophore-based 3D – QSAR Studies on Vitamin D Receptor (VDR)

2018 ◽  
Vol 21 (5) ◽  
pp. 329-343 ◽  
Author(s):  
Selvaraman Nagamani ◽  
Chandrasekhar Kesavan ◽  
Karthikeyan Muthusamy
Keyword(s):  
Vitamin D ◽  
Vitamin D Receptor ◽  
Binding Free Energy ◽  
3D Qsar ◽  
Free Energy Calculations ◽  
Biologically Active ◽  
Hydroxyl Group ◽  
Qsar Studies ◽  
Vitamin D Analogues ◽  
Semi Empirical

Aim and Objective: Vitamin D3 (1,25(OH)2D3) is a biologically active metabolite and plays a wide variety of regulatory functions in human systems. Currently, several Vitamin D analogues have been synthesized and tested against VDR (Vitamin D Receptor). Electrostatic potential methods are greatly influence the structure-based drug discovery. In this study, ab inito (DFT, HF, LMP2) and semi-empirical (RM1, AM1, PM3, MNDO, MNDO/d) charges were examined on the basis of their concert in predicting the docking pose using Induced Fit Docking (IFD) and binding free energy calculations against the VDR. Materials and Methods: Initially, we applied ab initio and semi-empirical charges to the 38 vitamin D analogues. Further, the charged analogues have been docked in the VDR active site. We generated the structure-based 3D-QSAR from the docked conformation of vitamin D analogues. On the other hand, we performed pharmacophore-based 3D-QSAR. Results: The result shows that, AM1 is the good charge model for our study and AM1 charge based QSAR produced more accurate ligand poses. Furthermore, the hydroxyl group in the side chain of vitamin D analogues played an important role in the VDR antagonistic activity. Conclusion: Overall, we found that charge-based optimizations of ligands were out performed than the pharmacophore based QSAR model.

3D-QSAR Studies on C24-Monoalkylated Vitamin D3 26,23-Lactones and their C2α-Modified Derivatives with Inhibitory Activity to Vitamin D Receptor

2010 ◽  
Vol 29 (8-9) ◽  
pp. 621-632 ◽  
Author(s):  
Jinhu Wang ◽  
Ke Tang ◽  
Qianqian Hou ◽  
Xueli Cheng ◽  
Lihua Dong ◽  
...  
Keyword(s):  
Vitamin D ◽  
Vitamin D Receptor ◽  
Vitamin D3 ◽  
Inhibitory Activity ◽  
3D Qsar ◽  
Qsar Studies

scholarly journals Dystrobrevin alpha gene is a direct target of the vitamin D receptor in muscle

2020 ◽  
Vol 64 (3) ◽  
pp. 195-208 ◽  
Author(s):  
Maria K Tsoumpra ◽  
Shun Sawatsubashi ◽  
Michihiro Imamura ◽  
Seiji Fukumoto ◽  
Shin’ichi Takeda ◽  
...  
Keyword(s):  
Vitamin D ◽  
Vitamin D Receptor ◽  
Target Genes ◽  
Musculoskeletal Diseases ◽  
Myogenic Differentiation ◽  
Biologically Active ◽  
Site Directed Mutagenesis ◽  
C2c12 Cells ◽  
Expression Vectors ◽  
Gene And Protein Expression

The biologically active metabolite of vitamin D, 1,25-dihydroxyvitamin D3 (VD3), exerts its tissue-specific actions through binding to its intracellular vitamin D receptor (VDR) which functions as a heterodimer with retinoid X receptor (RXR) to recognize vitamin D response elements (VDRE) and activate target genes. Upregulation of VDR in murine skeletal muscle cells occurs concomitantly with transcriptional regulation of key myogenic factors upon VD3 administration, reinforcing the notion that VD3 exerts beneficial effects on muscle. Herein we elucidated the regulatory role of VD3/VDR axis on the expression of dystrobrevin alpha (DTNA), a member of dystrophin-associated protein complex (DAPC). In C2C12 cells, Dtna and VDR gene and protein expression were upregulated by 1–50 nM of VD3 during all stages of myogenic differentiation. In the dystrophic-derived H2K-mdx52 cells, upregulation of DTNA by VD3 occurred upon co-transfection of VDR and RXR expression vectors. Silencing of MyoD1, an E-box binding myogenic transcription factor, did not alter the VD3-mediated Dtna induction, but Vdr silencing abolished this effect. We also demonstrated that VD3 administration enhanced the muscle-specific Dtna promoter activity in presence of VDR/RXR only. Through site-directed mutagenesis and chromatin immunoprecipitation assays, we have validated a VDRE site in Dtna promoter in myogenic cells. We have thus proved that the positive regulation of Dtna by VD3 observed during in vitro murine myogenic differentiation is VDR mediated and specific. The current study reveals a novel mechanism of VDR-mediated regulation for Dtna, which may be positively explored in treatments aiming to stabilize the DAPC in musculoskeletal diseases.

scholarly journals 1α,24(S)-dihydroxyvitamin D2: a biologically active product of 1α-hydroxyvitamin D2 made in the human hepatoma, Hep3B

1995 ◽  
Vol 310 (1) ◽  
pp. 233-241 ◽  
Author(s):  
S Strugnell ◽  
V Byford ◽  
H L J Makin ◽  
R M Moriarty ◽  
R Gilardi ◽  
...  
Keyword(s):  
Vitamin D ◽  
Biological Properties ◽  
Crystallographic Analysis ◽  
Biologically Active ◽  
Hydroxyl Group ◽  
X Ray ◽  
Metabolic Bone ◽  
Vitamin D Analogue ◽  
Made In

A major metabolite of the vitamin D analogue 1 alpha-hydroxyvitamin D2 in human liver cells in culture has been identified as 1 alpha,24(S)-dihydroxyvitamin D2 [1 alpha,24(S)-(OH)2D2]. 1 alpha-Hydroxyvitamin D3 incubated with the same cells gives rise to predominantly 25- and 27-hydroxylated products. Our identification of 1 alpha,24(S)-dihydroxyvitamin D2 is based on comparisons of the liver cell metabolite with chemically synthesized 1 alpha,24(S)-(OH)2D2 and 1 alpha,24(R)-(OH)2D2 by using HPLC, GC and GC-MS techniques. The stereochemical orientation of the 24-hydroxyl group was inferred after X-ray-crystallographic analysis of the 24(R)-OH epimer. 1 alpha,24(S)-Dihydroxyvitamin D2 binds strongly to the vitamin D receptor and is biologically active in growth hormone and chloramphenicol acetyltransferase reporter gene expression systems in vitro, but binds poorly to rat vitamin D-binding globulin, DBP. We suggest that this metabolite, 1 alpha,24(S)-(OH)2D2, possesses the spectrum of biological properties to be useful as a drug in the treatment of psoriasis, metabolic bone disease and cancer.

Potent Antagonist for the Vitamin D Receptor: Vitamin D Analogues with Simple Side Chain Structure

2010 ◽  
Vol 53 (15) ◽  
pp. 5813-5826 ◽  
Author(s):  
Yuta Sakamaki ◽  
Yuka Inaba ◽  
Nobuko Yoshimoto ◽  
Keiko Yamamoto
Keyword(s):  
Vitamin D ◽  
Vitamin D Receptor ◽  
Chain Structure ◽  
Side Chain ◽  
Vitamin D Analogues ◽  
Potent Antagonist

scholarly journals Potential Ebola drug targets – filling the gap: a critical step forward towards the design and discovery of potential drugs

Biologia ◽  
2017 ◽  
Vol 72 (1) ◽  
pp. 1-13 ◽  
Author(s):  
Marissa Balmith ◽  
Mahmoud E.S. Soliman
Keyword(s):  
Binding Site ◽  
Active Site ◽  
Active Sites ◽  
Binding Free Energy ◽  
Three Dimensional ◽  
Computational Prediction ◽  
Homology Model ◽  
Free Energy Calculations ◽  
Biologically Active ◽  
World Health

AbstractAmong the classified neglected infectious diseases, the Ebola virus (EboV) remains a challenging epidemic. This deadly virus has been reported as a category A bioweapon organism by the World Health Organization due to the serious threat it poses. To date, Ebola drug discovery proves challenging. Proteins need to be targeted at the relevant biologically active site for drug or inhibitor binding to be effective. Due to insufficient experimental data to confirm the biologically active binding site for novel protein targets, researchers often rely on computational prediction methods to identify binding sites. Many computational studies have attempted to identify the biological active site for EboV proteins, however, the methods employed are not sufficiently validated. This has prompted us to provide a comprehensive molecular understanding of the various targets of the EboV, including three-dimensional structures, active site identification and further validation. Herein we report the account of a three-dimensional homology model of the unresolved EboV RNA-dependent RNA polymerase (RdRp), as well as a comprehensive analysis of the binding site residues of all proteins of the EboV. Docking-aided active site determination was carried out to identify possible active sites on the homology model of RdRp. Binding free energy calculations revealed subtle differences in the binding at each site. These results can also provide some potential clues for further design of novel inhibitors to treat this killer virus and is a critical cornerstone of research into the EboV.

scholarly journals Mapping the Domains of the Interaction of the Vitamin D Receptor and Steroid Receptor Coactivator-1

1998 ◽  
Vol 12 (1) ◽  
pp. 57-65 ◽  
Author(s):  
Rajbir K. Gill ◽  
Loretta M. Atkins ◽  
Bruce W. Hollis ◽  
Norman H. Bell
Keyword(s):  
Vitamin D ◽  
Mutation Analysis ◽  
Vitamin D Receptor ◽  
Deletion Mutant ◽  
Active Form ◽  
Steroid Receptor ◽  
Deletion Mutation ◽  
Biologically Active ◽  
Dependent Manner ◽  
Steroid Receptor Coactivator

Abstract The vitamin D receptor (VDR) binds to the vitamin D response element (VDRE) and mediates the effects of the biologically active form of vitamin D, 1,25-dihydroxyvitamin D3[ 1,25-(OH)2D3], on gene expression. The VDR binds to the VDRE as a heterodimeric complex with retinoid X receptor. In the present study, we have used a yeast two-hybrid system to clone complementary DNA that codes for VDR-interacting protein(s). We found that the human steroid receptor coactivator-1 (SRC-1) interacts with the VDR in a ligand-dependent manner, as demonstrated by β-galactosidase production. The interaction of the VDR and the SRC-1 takes place at physiological concentrations of 1,25(OH)2D3. A 48.2-fold stimulation of β-galactosidase activity was observed in the presence of 10−10m 1,25-(OH)2D3. In addition, a direct interaction between the ligand-activated glutathione-S-transferase-VDR and 35S-labeled SRC-1 was observed in vitro. Deletion-mutation analysis of the VDR established that the ligand-dependent activation domain (AF-2) of the VDR is required for the interaction with SRC-1. One deletion mutant, pGVDR-(1–418), bound the ligand but failed to interact with the SRC-1, whereas another deletion mutant, pGVDR-(1–423), bound the ligand and interacted with the SRC-1. We demonstrated that all the deletion mutants were expressed as analyzed by a Gal4 DNA-binding domain antibody. Deletion mutation analysis of the SRC-1 demonstrated that 27 amino acids (DPCNTNPTPMTKATPEEIKLEAQS-QFT) of the SRC-1 are essential for interaction with the AF-2 motif of the VDR.

scholarly journals Vitamin D Receptor-Dependent Inhibition of Mammary Tumor Growth by EB1089 and Ultraviolet Radiation in Vivo

Endocrinology ◽  
2007 ◽  
Vol 148 (10) ◽  
pp. 4887-4894 ◽  
Author(s):  
Meggan E. Valrance ◽  
Andrea H. Brunet ◽  
JoEllen Welsh
Keyword(s):  
Vitamin D ◽  
Tumor Growth ◽  
Tumor Cells ◽  
Vitamin D Receptor ◽  
Biologically Active ◽  
Uv Exposure ◽  
Inhibit Tumor Growth ◽  
Antitumor Effects ◽  
Vitamin D Signaling

1,25-Dihydroxyvitamin D3 (1,25D), the biologically active form of vitamin D3, exerts antiproliferative and proapoptotic effects in multiple transformed cell types, and thus, the vitamin D signaling pathway represents a potential anticancer target. Although chronic treatment with 1,25D induces hypercalcemia, synthetic vitamin D analogs have been developed that inhibit tumor growth in vivo with minimal elevation of serum calcium. Furthermore, vitamin D is synthesized in skin exposed to UV light, and this route of vitamin D elevation is not associated with hypercalcemia. In this study, we examined whether enhancement of vitamin D status via exogenous (EB1089, a 1,25D analog) or endogenous (UV exposure) approaches could exert antitumor effects without hypercalcemia. We used mammary xenografts with differential vitamin D receptor (VDR) expression to examine whether the antitumor effects of either therapy are receptor mediated. We present evidence that both EB1089 and UV exposure inhibit tumor growth via induction of growth arrest and apoptosis. These antitumor effects were observed only in xenografts containing VDR-positive tumor cells; heterogeneous tumors containing VDR-negative tumor cells and VDR-positive stromal and endothelial cells were unresponsive to both therapies. No evidence for antiangiogenic effects of EB1089 were detected in this model system. Neither EB1089 nor UV was associated with overt toxicity, but keratinocyte proliferation was increased in UV-exposed skin. These data provide proof of principle that UV exposure modulates tumor growth via elevation of vitamin D signaling and that therapeutic approaches designed to target the vitamin D pathway will be effective only if tumor cells express functional VDR.

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