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1.
Mol Cell Endocrinol ; 485: 1-8, 2019 04 05.
Artigo em Inglês | MEDLINE | ID: mdl-30654005

RESUMO

In recent decades, the majority of ligands developed for the vitamin D receptor (VDR) bind at its deeply buried genomic ligand binding pocket. Theses ligands can be categorized into agonists and partial agonists/antagonists. A limited number of ligands, most of them peptides, bind the VDR‒coactivator binding site that is formed in the presence of an agonist and inhibit coactivator recruitment, and therefore transcription. Another solvent exposed VDR‒ligand binding pocket was identified for lithocholic acid, improving the overall stability of the VDR complex. Additional proposed interactions with VDR are discussed herein that include the alternative VDR‒ligand binding pocket that may mediate both non-genomic cellular responses and binding function 3 that was identified for the androgen receptor. Many VDR ligands increase blood calcium levels at therapeutic concentrations in vivo, thus the identification of alternative VDR‒ligand binding pockets might be crucial to develop non-calcemic and potent ligands for VDR to treat cancer and inflammatory disease.


Assuntos
Peptídeos/química , Peptídeos/farmacologia , Receptores de Calcitriol/química , Receptores de Calcitriol/metabolismo , Animais , Sítios de Ligação , Cálcio/sangue , Humanos , Ligantes , Modelos Moleculares , Ligação Proteica , Estrutura Terciária de Proteína , Relação Estrutura-Atividade
2.
J Steroid Biochem Mol Biol ; 187: 118-123, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30468856

RESUMO

In higher metazoans, the nuclear hormone receptors activate transcription trough their specific adaptors, nuclear hormone receptor adaptors NCoA, which are absent in lower metazoans. The Nine amino acid TransActivation Domain, 9aaTAD, was reported for a large number of the transcription activators that recruit general mediators of transcription. In this study, we demonstrated that the 9aaTAD from NHR-49 receptor of nematode C.elegans activates transcription as a small peptide. We showed that the ancient 9aaTAD domains are conserved in the nuclear hormone receptors including human HNF4, RARa, VDR and PPARg. Also their small 9aaTAD peptides effectively activated transcription in absence of the NCoA adaptors. We also showed that adjacent H11 domains in ancient and modern hormone receptors have an inhibitory effect on their 9aaTAD function.


Assuntos
Receptores Citoplasmáticos e Nucleares/metabolismo , Ativação Transcricional , Sequência de Aminoácidos , Animais , Caenorhabditis elegans/química , Caenorhabditis elegans/metabolismo , Proteínas de Caenorhabditis elegans/química , Proteínas de Caenorhabditis elegans/metabolismo , Fator 4 Nuclear de Hepatócito/química , Fator 4 Nuclear de Hepatócito/metabolismo , Humanos , Modelos Moleculares , PPAR gama/química , PPAR gama/metabolismo , Peptídeos/química , Peptídeos/metabolismo , Domínios Proteicos , Receptores de Calcitriol/química , Receptores de Calcitriol/metabolismo , Receptores Citoplasmáticos e Nucleares/química , Receptor alfa de Ácido Retinoico/química , Receptor alfa de Ácido Retinoico/metabolismo , Alinhamento de Sequência , Transdução de Sinais
3.
J Mol Graph Model ; 86: 132-141, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30359859

RESUMO

Combination of dopamine D3 antagonism and serotonin 5-HT1A agonism leads to an effective way to atypical antipsychotics. In this work, two predictive 3D-QSAR models were bulit for D3R antagonists and 5-HT1AR agonists, respectively. Based on the steric and electrostatic information of contour maps, four compounds with improved predicted activities were newly designed. In addition, molecular docking and ADMET properties suggested that designed molecules had strong interactions with receptors and low hepatotoxicity. This work sheds light on the design of bifunctional novel antipsychotic drugs for D3R antagonists and 5HT1AR agonists.


Assuntos
Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Relação Quantitativa Estrutura-Atividade , Receptor 5-HT1A de Serotonina/química , Receptores de Calcitriol/química , Agonistas do Receptor 5-HT1 de Serotonina/química , Modelos Teóricos , Estrutura Molecular , Receptores de Calcitriol/antagonistas & inibidores , Agonistas do Receptor 5-HT1 de Serotonina/farmacologia
4.
J Steroid Biochem Mol Biol ; 186: 89-95, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30278216

RESUMO

Vitamin D is recognized to play important roles in the onset of immunological diseases as well as the regulation of the amount of Ca in the blood. Since these physiological actions caused by active vitamin D are triggered by the specific interaction between the vitamin D receptor (VDR) and active vitamin D, many types of compounds have been developed as potent ligands against VDR. It was found that the binding affinity between VDR and its ligand depends significantly on the chirality of the ligand. However, the reason for the dependence has, thus far, not been elucidated. In the present study, we investigated the specific interactions between VDR and some ligands with different chirality, using ab initio fragment molecular orbital (FMO) calculations. The FMO results reveal that two histidine residues of VDR contribute significantly to the binding between VDR and ligand and that their protonation states can affect the specific interactions between VDR and ligand. We therefore considered other possible protonation states of these histidine residues and determined their most stable states, using the ab initio FMO calculations. The results illustrate the possibility that the difference in the chirality of a ligand can induce the change in protonation states of the histidine residues of VDR existing near the ligand. This finding provides an important warning that the protonation states of histidine residues existing near the ligand should be considered more precisely in the molecular simulations for investigating the specific interactions between protein and ligand.


Assuntos
Histidina/química , Receptores de Calcitriol/química , Água/química , Histidina/metabolismo , Humanos , Ligantes , Simulação de Acoplamento Molecular , Ligação Proteica , Prótons , Receptores de Calcitriol/metabolismo , Estereoisomerismo , Termodinâmica , Água/metabolismo
5.
J Med Chem ; 61(23): 10573-10587, 2018 12 13.
Artigo em Inglês | MEDLINE | ID: mdl-30350999

RESUMO

Liver fibrosis is characterized by excessive deposition of extracellular matrix (ECM) components and results in impaired liver function. Vitamin D plays a critical role in the development of liver fibrosis as it inhibits transforming growth factor ß1 (TGFß1)-induced excessive deposition of ECM in activated hepatic stellate cells (HSCs). Here, a series of novel nonsecosteroidal vitamin D receptor (VDR) agonists with phenyl-pyrrolyl pentane skeleton was designed and synthesized. Among them, seven compounds including 15a exhibited more efficient inhibitory activity in collagen deposition and fibrotic gene expression. Histological examination results displayed that compound 15a treatment prevented the development of hepatic fibrosis that induced by carbon tetrachloride (CCl4) injections in mice. In addition, compound 15a, unlike the positive control calcipotriol and 1,25(OH)2D3, did not cause hypercalcemia that is toxic to nerve, heart, and many other organs. These findings provide novel insights into drug discoveries for hepatic fibrosis using nonsecosteroidal VDR modulators.


Assuntos
Desenho de Fármacos , Cirrose Hepática/tratamento farmacológico , Pentanos/síntese química , Pentanos/farmacologia , Pirróis/química , Receptores de Calcitriol/agonistas , Animais , Linhagem Celular , Técnicas de Química Sintética , Fígado/efeitos dos fármacos , Fígado/metabolismo , Fígado/patologia , Fígado/fisiopatologia , Cirrose Hepática/metabolismo , Cirrose Hepática/fisiopatologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Modelos Moleculares , Pentanos/química , Pentanos/uso terapêutico , Conformação Proteica , Receptores de Calcitriol/química
6.
PLoS One ; 13(10): e0203194, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30286109

RESUMO

The level of the vitamin D in the bloodstream is regulated by cytochrome P450 enzyme 24-hydroxylase A1 (CYP24A1). Over expression of CYP24A1 enzyme is correlated with vitamin D deficiency and resistance to vitamin D therapy. Chronic kidney disease (CKD) patients are commonly reported with the above said expression variations. This deregulation could be solved by ligands that act as a vitamin D receptor (VDR) agonists and CYP24A1 antagonists. Posner et al., (2010) first time reported two new vitamin D analogues namely CTA-091 and CTA-018 to inhibit CYP24A1. The CTA-018 inhibited CYP24A1 with an IC50 27 ± 6 nM (10 times more potent than the ketoconazole (253 ± 20 nM)). CTA-018 induced VDR expression (15-fold lower than 1α,25(OH)2D3) and is under phase II clinical trial, whereas CTA-091 was not able to efficiently induce the VDR expression (>2000 nM). To explore the molecular mechanism, binding specificity of these two vitamin D analogues along with native ligand was extensively studied through in silico approaches. Through molecular dynamics simulations studies, we shown that the sulfonic group (O = S = O) in the side chain of CTA-018 plays an important role in the regulation of VDR agonistic activity. The electron lone pairs of the sulfonic group that interacted with His393 lead to be a factor for agonistic mechanism of VDR activity. Compared to azol-based compounds, CTA-018 binds the different sites in the CYP24A1 binding cavity and thus it could be a potent antagonistic for CYP24A1enzyme.


Assuntos
Receptores de Calcitriol/química , Insuficiência Renal Crônica/tratamento farmacológico , Deficiência de Vitamina D/tratamento farmacológico , Vitamina D3 24-Hidroxilase/química , Vitamina D/química , Humanos , Ligação de Hidrogênio , Cetoconazol/administração & dosagem , Ligantes , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Conformação Proteica , Receptores de Calcitriol/agonistas , Receptores de Calcitriol/genética , Insuficiência Renal Crônica/sangue , Insuficiência Renal Crônica/genética , Vitamina D/análogos & derivados , Deficiência de Vitamina D/sangue , Deficiência de Vitamina D/genética , Vitamina D3 24-Hidroxilase/antagonistas & inibidores , Vitamina D3 24-Hidroxilase/genética
7.
J Med Chem ; 61(15): 6658-6673, 2018 Aug 09.
Artigo em Inglês | MEDLINE | ID: mdl-29989817

RESUMO

Both 25 R- and 25 S-25-adamantyl-23-yne-26,27-dinor-1α,25-dihydroxyvitamin D3 (4a and 4b) were stereoselectively synthesized by a Pd(0)-catalyzed ring closure and Suzuki-Miyaura coupling between enol-triflate 7 and alkenyl-boronic ester 8. The 25 S isomer (4b) showed high vitamin D receptor (VDR) affinity (50% of that of the natural hormone 1α,25-dihydroxyvitamin D3, 1) and transactivation potency (kidney HEK293, 90%). In endogenous gene expression, it showed high cell-type selectivity for kidney cells (HEK293, CYP24A1 160% of 1), bone cells (MG63, osteocalcin 64%), and monocytes (U937, CAMP 96%) over intestine (SW480, CYP24A1 8%) and skin (HaCaT, CYP24A1 7%) cells. The X-ray crystal structural analysis of 4b in complex with rat VDR-ligand binding domain (LBD) showed the highest Cα positional shift from the 1/VDR-LBD complex at helix 11. Helix 11 of the 4b and 1 VDR-LBD complexes also showed significant differences in surface properties. These results suggest that 4b should be examined further as another candidate for a mild preventive osteoporosis agent.


Assuntos
Receptores de Calcitriol/química , Receptores de Calcitriol/metabolismo , Vitamina D/análogos & derivados , Transporte Biológico , Técnicas de Química Sintética , Cristalografia por Raios X , Células HEK293 , Humanos , Receptores de Calcitriol/genética , Estereoisomerismo , Transcrição Genética/efeitos dos fármacos , Vitamina D/síntese química , Vitamina D/química , Vitamina D/metabolismo , Vitamina D/farmacologia
8.
Comb Chem High Throughput Screen ; 21(5): 329-343, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29874993

RESUMO

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.


Assuntos
Simulação de Acoplamento Molecular/métodos , Receptores de Calcitriol/química , Vitamina D/química , Sítios de Ligação , Bases de Dados de Proteínas , Desenho de Fármacos , Ligantes , Conformação Molecular , Ligação Proteica , Relação Quantitativa Estrutura-Atividade , Eletricidade Estática , Termodinâmica , Vitamina D/análogos & derivados
9.
J Med Chem ; 61(14): 6339-6349, 2018 Jul 26.
Artigo em Inglês | MEDLINE | ID: mdl-29936834

RESUMO

We designed and synthesized vitamin D analogues with an electrophile as covalent modifiers for the vitamin D receptor (VDR). Novel vitamin D analogues 1-4 have an electrophilic enone group at the side chain for conjugate addition to His301 or His393 in the VDR. All compounds showed specific VDR-binding potency and agonistic activity. Covalent bond formations of 1-4 with the ligand-binding domain (LBD) of VDR were evaluated by electrospray ionization mass spectrometry. All compounds were shown to covalently bind to the VDR-LBD, and the abundance of VDR-LBD corresponding conjugate adducts of 1-4 increased with incubation time. Enone compounds 1 and 2 showed higher reactivity than the ene-ynone 3 and dienone 4 compounds. Furthermore, we successfully obtained cocrystals of VDR-LBD with analogues 1-4. X-ray crystallographic analysis showed a covalent bond with His301 in VDR-LBD. We successfully synthesized vitamin D analogues that form a covalent bond with VDR-LBD.


Assuntos
Desenho de Fármacos , Histidina , Receptores de Calcitriol/química , Receptores de Calcitriol/metabolismo , Humanos , Ligantes , Modelos Moleculares , Ligação Proteica , Domínios Proteicos
10.
Org Biomol Chem ; 16(14): 2448-2455, 2018 04 04.
Artigo em Inglês | MEDLINE | ID: mdl-29560490

RESUMO

Both 2α- and 2ß-hydroxypropyl substituted 14-epi-1α,25-dihydroxy-19-nortachysterols were synthesized to study the human vitamin D receptor (hVDR) binding affinity, binding configurations, and interactions with amino acid residues in the ligand binding domain of hVDR by X-ray co-crystallographic analysis. In conjunction with our previous results on 14-epi-19-nortachysterol, 2-methylidene-, 2α-methyl-, 2ß-methyl, and 2α-hydroxypropoxy-14-epi-19-nortachysterol, we propose a variety of effects of substitution at the C2 position in the 14-epi-19-nortachysterol skeleton on biological activities.


Assuntos
Colecalciferol/análogos & derivados , Receptores de Calcitriol/química , Sítios de Ligação , Colecalciferol/síntese química , Colecalciferol/química , Cristalografia por Raios X , Humanos , Ligantes , Estrutura Molecular
11.
J Mol Graph Model ; 81: 14-24, 2018 05.
Artigo em Inglês | MEDLINE | ID: mdl-29476931

RESUMO

Pharmacogenetics and pharmacogenomics have become presumptive with advancements in next-generation sequencing technology. In complex diseases, distinguishing the feasibility of pathogenic and neutral disease-causing variants is a time consuming and expensive process. Recent drug research and development processes mainly rely on the relationship between the genotype and phenotype through Single nucleotide polymorphisms (SNPs). The SNPs play an indispensable role in elucidating the individual's vulnerability to disease and drug response. The understanding of the interplay between these leads to the establishment of personalized medicine. In order to address this issue, we developed a computational pipeline of vitamin D receptor (VDR) for SNP centered study by application of elegant molecular docking and molecular dynamics simulation approaches. In a few SNPs the volume of the binding cavities has increased in mutant structures when compared to the wild type, indicating a weakening in interaction (699.1 Å3 in wild type Vs. 738.8 in Leu230Val, 820.7 Å3 in Arg247Leu). This also differently reflected in the H-bond interactions and binding free energies -169.93 kcal/mol (wild type) Vs -156.43 kcal/mol (R154W), -105.49 kcal/mol (R274L) in Leu230Val and Arg247Leu respectively. Although we could not find noteworthy changes in the binding free energies and binding pocket in the remaining mutations, the H-bond interactions made these SNPs deleterious. Thus, we further analyzed the H-bond interactions and distances using molecular dynamics (MD) simulation studies.


Assuntos
Calcitriol/química , Polimorfismo de Nucleotídeo Único , Receptores de Calcitriol/química , Receptores de Calcitriol/genética , Sequência de Aminoácidos , Sítios de Ligação , Humanos , Ligantes , Conformação Molecular , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Mutação , Ligação Proteica , Relação Estrutura-Atividade
12.
J Mol Graph Model ; 80: 320-326, 2018 03.
Artigo em Inglês | MEDLINE | ID: mdl-29433089

RESUMO

Vitamin D plays an important role in the regulation of the calcium and phosphorus metabolism as well as in bone formation. These physiological actions caused by vitamin D are triggered by the specific binding of vitamin D to its receptor (VDR). Here we investigated the specific interactions and binding affinities between VDR and vitamin D derivatives, using ab initio fragment molecular orbital (FMO) calculations. The FMO results elucidate that relative position of the two hydroxyl groups of the derivatives is essential for the strong binding affinity between the derivative and Arg274 residue of VDR. It is therefore expected that novel potent ligands, which have a great binding affinity for VDR, are developed by adjusting the positions of the hydroxyl groups in the derivatives in such a way as these groups form strong hydrogen bonds with VDR residues. We proposed these novel derivatives and investigated their specific interactions with VDR at atomic and electronic levels to obtain a more potent ligand for VDR.


Assuntos
Modelos Moleculares , Receptores de Calcitriol/química , Colecalciferol/química , Ligantes , Conformação Molecular , Estrutura Molecular , Ligação Proteica , Receptores de Calcitriol/antagonistas & inibidores , Relação Estrutura-Atividade
13.
Curr Med Chem ; 25(27): 3256-3271, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29446731

RESUMO

BACKGROUND: Kidney disease is a serious problem that adversely affects human health, but critical knowledge is lacking on how to effectively treat established chronic kidney disease. Mounting evidence from animal and clinical studies has suggested that Vitamin D Receptor (VDR) activation has beneficial effects on various renal diseases. METHODS: A structured search of published research literature regarding VDR structure and function, VDR in various renal diseases (e.g., IgA nephropathy, idiopathic nephrotic syndrome, renal cell carcinoma, diabetic nephropathy, lupus nephritis) and therapies targeting VDR was performed for several databases. RESULT: Included in this study are the results from 177 published research articles. Evidence from these papers indicates that VDR activation is involved in the protection against renal injury in kidney diseases by a variety of mechanisms, including suppression of RAS activation, anti-inflammation, inhibiting renal fibrogenesis, restoring mitochondrial function, suppression of autoimmunity and renal cell apoptosis. CONCLUSION: VDR offers an attractive druggable target for renal diseases. Increasing our understanding of VDR in the kidney is a fertile area of research and may provide effective weapons in the fight against kidney diseases.


Assuntos
Anti-Inflamatórios/farmacologia , Anti-Inflamatórios/uso terapêutico , Nefropatias/tratamento farmacológico , Nefropatias/metabolismo , Receptores de Calcitriol/antagonistas & inibidores , Animais , Humanos , Receptores de Calcitriol/química , Receptores de Calcitriol/metabolismo
14.
Mol Cell Endocrinol ; 472: 18-25, 2018 09 05.
Artigo em Inglês | MEDLINE | ID: mdl-29183808

RESUMO

Vitamin D is best known for its regulation of calcium homeostasis. Vitamin D exerts its genomic actions via the vitamin D receptor (VDR). As a member of the superfamily of nuclear receptors (NR), the VDR is primarily located within the nucleus of non-dividing cells. We show here that the VDR relocates from the nucleus into the cytoplasm across all stages of cell division in CHO cells. Furthermore, we show that the VDR is transcriptionally inert during cell division. In addition, 1α, 25 dihydroxyvitamin D (1,25(OH)2D3) promotes VDR binding to the nuclear matrix. Finally, we assessed the structural nature of VDR binding to the nuclear matrix. Mutation of the hinge domain reduced VDR's ability to bind to the nuclear matrix and to initiate transcription in response to 1,25(OH)2D3. Taken together, our data suggest that the association between the VDR and the nuclear matrix accounts for the apparent cytosolic distribution as the matrix disperses within the cytoplasm when cells divide. This may also explain the dramatic reduction in VDR mediated transcription during cell division. Our data also confirm that similar to other NRs, the hinge domain of the VDR is responsible for this association.


Assuntos
Mitose/genética , Matriz Nuclear/metabolismo , Receptores de Calcitriol/química , Receptores de Calcitriol/metabolismo , Transcrição Genética , Animais , Células CHO , Calcitriol/farmacologia , Cricetinae , Cricetulus , Regulação da Expressão Gênica/efeitos dos fármacos , Interfase/efeitos dos fármacos , Mitose/efeitos dos fármacos , Mutação/genética , Matriz Nuclear/efeitos dos fármacos , Ligação Proteica/efeitos dos fármacos , Domínios Proteicos , Ratos , Relação Estrutura-Atividade , Transcrição Genética/efeitos dos fármacos
15.
Gynecol Endocrinol ; 34(2): 161-165, 2018 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-28868946

RESUMO

Polycystic ovary syndrome (PCOS) is the most common endocrine disorder of reproductive age women. Emerging evidence suggests that Vitamin D Receptor (VDR) might be a causal factor for characteristics associated with PCOS such as obesity and type 2 diabetes. Present study investigated association between VDR gene BsmI A/G (rs1544410), ApaI A/C (rs7975232) and TaqI T/C (rs731236) single nucleotide polymorphisms and PCOS risk in South Indian women. Genotyping of VDR gene SNPs was carried out in PCOS patients (n = 95) and controls (n = 130) by PCR-RFLP method and confirmed by sequencing analysis. Haplotype frequencies for multiple loci and the standardized disequilibrium coefficient (D') for pairwise linkage disequilibrium (LD) were assessed by Haploview software. Results showed significantly increased frequencies of BsmI G/G (p = .0197), ApaI C/C (p = .048), TaqI C/C (p = .044) genotypes and BsmI G (p = .0181), ApaI C (p = .0092), TaqI C (p = .0066) alleles in patients compared to controls. In addition, the frequency of the 'BsmI G, ApaI C, TaqI C' haplotype was also significantly elevated in patients (p = .0087). In conclusion, the VDR gene BsmI A/G ApaI A/C TaqI T/C and haplotype may constitute an inheritable risk factor for PCOS in South Indian women.


Assuntos
Predisposição Genética para Doença , Síndrome do Ovário Policístico/genética , Receptores de Calcitriol/genética , Adulto , Alelos , Índice de Massa Corporal , Estudos de Casos e Controles , Éxons , Feminino , Frequência do Gene , Estudos de Associação Genética , Heterozigoto , Humanos , Índia , Infertilidade Feminina/etiologia , Íntrons , Desequilíbrio de Ligação , Análise por Pareamento , Síndrome do Ovário Policístico/metabolismo , Síndrome do Ovário Policístico/fisiopatologia , Polimorfismo de Nucleotídeo Único , Receptores de Calcitriol/química , Receptores de Calcitriol/metabolismo , Análise de Sequência de DNA
16.
J Steroid Biochem Mol Biol ; 177: 231-234, 2018 03.
Artigo em Inglês | MEDLINE | ID: mdl-28823515

RESUMO

Pronounced biological potency of 19-norvitamin D compounds as well as interesting biological action of the vitamin D analogs possessing elongated side chains encouraged us to expand the scope of our structure-activity studies to encompass such modifications of the 1α,25-(OH)2D3 (calcitriol) molecule. The aim of our studies was the synthesis of calcitriol analog, designed on the basis of results of molecular modeling and docking experiments, and characterized by a presence of a long, nitrogen-containing substituent attached to carbon 26, and an exomethylene moiety transferred from C-10 to C-2. The convergent synthesis of such 19-norcalcitriol compound, described in this communication, consisted of the preparation and combining four building blocks. The crucial point of the synthesis, coupling of the known A-ring phosphine oxide and the synthesized Grundmann ketone analog, was achieved using Wittig-Horner protocol. It provided the protected analog of 1α,25-dihydroxy-2-methylene-19-norvitamin D3 which was further transformed into the target compound.


Assuntos
Calcitriol/análogos & derivados , Calcitriol/química , Modelos Moleculares , Receptores de Calcitriol/química
17.
J Steroid Biochem Mol Biol ; 177: 235-239, 2018 03.
Artigo em Inglês | MEDLINE | ID: mdl-28756293

RESUMO

On the basis of the literature data, our previous research work and docking experiments, we designed novel 19-norvitamin D compounds having elongated 2-alkylidene substituents. These 19-norcalcitriol derivatives have attached 2-(3'-aminopropylidene) substituent in which the nitrogen atom bears acyl residue derived from succinic acid and l-methionine. Both compounds were obtained by the same synthetic strategy involving Julia coupling of the A-ring ketone with the known C/D-ring sulfone. In the obtained 1α,25-dihydroxy-19-norvitamin D3 derivative, the alkylidene substituent at C-2 was further elaborated to the desired structures.


Assuntos
Calcitriol/análogos & derivados , Calcitriol/química , Metionina/química , Simulação de Acoplamento Molecular , Receptores de Calcitriol/química , Ácido Succínico/química
18.
Nat Commun ; 8(1): 923, 2017 10 13.
Artigo em Inglês | MEDLINE | ID: mdl-29030554

RESUMO

The vitamin D receptor/retinoid X receptor-α heterodimer (VDRRXRα) regulates bone mineralization via transcriptional control of osteocalcin (BGLAP) gene and is the receptor for 1α,25-dihydroxyvitamin D3 (1,25D3). However, supra-physiological levels of 1,25D3 activates the calcium-regulating gene TRPV6 leading to hypercalcemia. An approach to attenuate this adverse effect is to develop selective VDR modulators (VDRMs) that differentially activate BGLAP but not TRPV6. Here we present structural insight for the action of a VDRM compared with agonists by employing hydrogen/deuterium exchange. Agonist binding directs crosstalk between co-receptors upon DNA binding, stabilizing the activation function 2 (AF2) surfaces of both receptors driving steroid receptor co-activator-1 (SRC1) interaction. In contrast, AF2 of VDR within VDRM:BGLAP bound heterodimer is more vulnerable for large stabilization upon SRC1 interaction compared with VDRM:TRPV6 bound heterodimer. These results reveal that the combination of ligand structure and DNA sequence tailor the transcriptional activity of VDR toward specific target genes.The vitamin D receptor/retinoid X receptor-α heterodimer (VDRRXRα) regulates bone mineralization. Here the authors employ hydrogen/deuterium exchange (HDX) mass spectrometry to study the conformational dynamics of VDRRXRα and give mechanistic insights into how VDRRXRα controls the transcriptional activity of specific genes.


Assuntos
DNA/química , Receptores de Calcitriol/química , Receptores de Calcitriol/metabolismo , DNA/genética , DNA/metabolismo , Medição da Troca de Deutério , Dimerização , Humanos , Hidrogênio , Ligantes , Espectrometria de Massas , Osteocalcina/genética , Osteocalcina/metabolismo , Ligação Proteica , Receptores de Calcitriol/genética , Receptores X Retinoide/química , Receptores X Retinoide/genética , Receptores X Retinoide/metabolismo , Vitamina D/análogos & derivados , Vitamina D/metabolismo
19.
Sci Rep ; 7(1): 14132, 2017 10 26.
Artigo em Inglês | MEDLINE | ID: mdl-29074956

RESUMO

Lysine succinylation, emerging as a novel post-translational modification, is closely related to the regulation of diverse biological processes, including many aspects of metabolism. Growing evidence suggests that low vitamin D status might exert an adverse impact on energy balance, adipogenesis and inflammation in white adipose tissue (WAT). However, whether there are any interactions between vitamin D and lysine succinylation still remains unknown. Here, combining high-affinity enrichment of lysine succinylated peptides with mass spectrometry and bioinformatics analysis, we reported the systematic profiling of the lysine succinylome, identifying 209 sites occurring on 159 proteins were up-regulated, 3 sites in 3 proteins were down-regulated in vitamin D receptor (VDR)-/- mice. Bioinformatics analysis reveals potential impacts of lysine succinylation on diverse biological processes and molecular functions, especially on carbon biotransformation, fatty acid metabolism and TCA cycle. Furthermore, eight unique motifs surrounding the succinylation sites were validated. Collectively, our findings demonstrate the first comprehensive profiling of WAT succinylome in VDR-/- mice, and provide crucial clues for further elucidating the underlying mechanisms of the involvement of the VDR in energy metabolism.


Assuntos
Tecido Adiposo Branco/metabolismo , Metabolismo Energético , Lisina/metabolismo , Processamento de Proteína Pós-Traducional , Receptores de Calcitriol/química , Receptores de Calcitriol/metabolismo , Motivos de Aminoácidos , Animais , Ciclo do Ácido Cítrico , Camundongos , Camundongos Endogâmicos C57BL
20.
Mol Med Rep ; 16(2): 1167-1172, 2017 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-29067439

RESUMO

Apolipoprotein M (ApoM) and the vitamin D receptor (VDR) are apolipoproteins predominantly presenting in high-density lipoprotein (HDL) and a karyophilic protein belonging to the steroid­thyroid receptor superfamily, respectively. Previous studies have demonstrated that ApoM and VDR are associated with cholesterol metabolism, immune and colorectal cancer regulation. In order to investigate whether ApoM affected the expression of VDR in colorectal cancer cells, a single­tube duplex fluorescence reverse transcription­quantitative polymerase chain reaction (RT­qPCR) system was developed to simultaneously detect the mRNA levels of VDR and GAPDH in HT­29 cells overexpressing ApoM. The results demonstrated that the amplification products were confirmed as the specific fragment of VDR/GAPDH using the DNA sequencing instrument. The sensitivity, linear range, correlation coefficient, amplification efficiency, intra­assay and inter­assay coefficients of variation were 40 copies/µl, 4.00x101­4.00x105 copies/µl, 0.999, 92.42%, 0.09­0.34% and 0.32­0.65% for VDR, and 40 copies/µl, 4.00x101­4.00x105 copies/µl, 0.999, 98.07%, 0.19­0.43% and 0.40­0.75% for GAPDH, respectively. The results indicated that the expression of VDR mRNA was significantly higher in HT­29 cells overexpressing ApoM, compared with the negative control group (P<0.05). In conclusion, the current study successfully developed the single­tube duplex RT­qPCR to simultaneously detect VDR and GAPDH expression in colorectal cancer cells. The methodology results demonstrated that the duplex RT­qPCR system with high sensitivity and specificity could ensure the objectivity and credibility of the detection. The present study confirmed that ApoM significantly increased the expression of VDR in HT­29 cells. In addition, it was hypothesized that ApoM may be involved in antineoplastic activity via the upregulation of VDR expression, which may provide novel directions for the investigation of ApoM in cancer.


Assuntos
Apolipoproteínas M/metabolismo , RNA Mensageiro/metabolismo , Receptores de Calcitriol/genética , Apolipoproteínas M/genética , Sequência de Bases , Neoplasias Colorretais/metabolismo , Neoplasias Colorretais/patologia , Gliceraldeído-3-Fosfato Desidrogenases/química , Gliceraldeído-3-Fosfato Desidrogenases/genética , Gliceraldeído-3-Fosfato Desidrogenases/metabolismo , Células HT29 , Humanos , Plasmídeos/genética , Plasmídeos/metabolismo , Receptores de Calcitriol/química , Receptores de Calcitriol/metabolismo , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Análise de Sequência de DNA , Regulação para Cima
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