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1.
Mol Pharm ; 20(3): 1631-1642, 2023 03 06.
Artigo em Inglês | MEDLINE | ID: mdl-36812406

RESUMO

The binding processes of two Polo-like kinase inhibitors, RO3280 and GSK461364, to the human serum albumin (HSA) protein as well as the protonation equilibria of both compounds have been studied combining absorbance and fluorescence spectroscopy experiments together with density functional theory calculations. We found that the charge states of RO3280 and GSK461364 are +2 and +1, respectively, at the physiological pH. Nevertheless, RO3280 binds to HSA in the charge state +1 prior to a deprotonation pre-equilibrium. Binding constants to site I of HSA of 2.23 × 106 and 8.80 × 104 M-1 were determined for RO3280 and GSK461364, respectively, at 310 K. The binding processes of RO3280 and GSK461364 to HSA are entropy- and enthalpy-driven, respectively. The positive enthalpy found for the RO3280-HSA complex formation could be related to a proton pre-equilibrium of RO3280.


Assuntos
Albumina Sérica Humana , Albumina Sérica , Humanos , Albumina Sérica/metabolismo , Ligação Proteica , Albumina Sérica Humana/metabolismo , Termodinâmica , Espectrometria de Fluorescência , Sítios de Ligação
2.
Mol Pharmacol ; 101(3): 144-153, 2022 03.
Artigo em Inglês | MEDLINE | ID: mdl-34969830

RESUMO

The G protein-coupled receptors form the most abundant family of membrane proteins and are crucial physiologic players in the homeostatic equilibrium, which we define as health. They also participate in the pathogenesis of many diseases and are frequent targets of therapeutic intervention. Considering their importance, it is not surprising that different mechanisms regulate their function, including desensitization, resensitization, internalization, recycling to the plasma membrane, and degradation. These processes are modulated in a highly coordinated and specific way by protein kinases and phosphatases, ubiquitin ligases, protein adaptors, interaction with multifunctional complexes, molecular motors, phospholipid metabolism, and membrane distribution. This review describes significant advances in the study of the regulation of these receptors by phosphorylation and endosomal traffic (where signaling can take place); we revisited the bar code hypothesis and include two additional observations: 1) that different phosphorylation patterns seem to be associated with internalization and endosome sorting for recycling or degradation, and 2) that, surprisingly, phosphorylation of some G protein-coupled receptors appears to be required for proper receptor insertion into the plasma membrane. SIGNIFICANCE STATEMENT: G protein-coupled receptor phosphorylation is an early event in desensitization/signaling switching, endosomal traffic, and internalization. These events seem crucial for receptor responsiveness, cellular localization, and fate (recycling/degradation) with important pharmacological/therapeutic implications. Phosphorylation sites vary depending on the cells in which they are expressed and on the stimulus that leads to such covalent modification. Surprisingly, evidence suggests that phosphorylation also seems to be required for proper insertion into the plasma membrane for some receptors.


Assuntos
Membrana Celular/metabolismo , Transdução de Sinais/fisiologia , Proteínas rab de Ligação ao GTP/metabolismo , Animais , Humanos , Fosforilação/fisiologia , Transporte Proteico/fisiologia , Receptores Acoplados a Proteínas G/metabolismo
3.
Gac Med Mex ; 158(2): 98-103, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35763825

RESUMO

Receptors are proteins coded by DNA, some of which have already been crystalized, thus allowing the details of their structure at the atomic level and some aspects of their function to be known. This review focuses on the most diverse and abundant family of receptors, G protein-coupled receptors. This family of receptors recognizes and mediates the action of several endogenous ligands (hormones, neurotransmitters, growth factors and local hormones) and also intervenes in the pathogenesis of various diseases, which is why they are targeted by approximately 30 to 40% of medications that are used in daily clinical practice and of various illegal drugs as well. X-ray crystallography is one of the essential tools that has allowed to observe the structure of these receptors in the amino acids that participate in this interaction, which allows to know the binding site of the endogenous ligand and of synthetic molecules that act on them to modulate their action. Molecular modeling or "docking" is also a computational bioinformatics tool that supports research on receptor-ligand binding, which allows the design and development of increasingly specific drugs. These developments have brought along significant changes in fundamental pharmacodynamic concepts.


Los receptores son proteínas codificadas por el ADN, algunos de los cuales ya han sido cristalizados, lo que permite conocer los detalles de su estructura a nivel atómico y algunos aspectos de su función. Esta revisión se enfoca en los más diversos y abundantes, los receptores acoplados a la proteína G. Esta familia de receptores reconoce y media la acción de varios ligandos endógenos (hormonas, neurotransmisores, factores de crecimiento y hormonas locales) y también interviene en la patogenia de diversas enfermedades, por lo que son el blanco terapéutico de aproximadamente 30 a 40 % de los medicamentos que se emplean en la práctica clínica cotidiana y de diversas drogas ilegales. La cristalografía de rayos X es una de las herramientas clave que ha permitido observar la estructura de estos receptores en los aminoácidos que participan en esta interacción, lo que posibilita conocer el sitio de unión del ligando endógeno y de moléculas sintéticas que actúan sobre ellos para modular su acción. El modelado molecular es también una herramienta bioinformática computacional que apoya la investigación sobre la unión receptor-ligando, que hace posible el diseño y desarrollo de fármacos cada vez más específicos. A estos desarrollos se suman importantes cambios en los conceptos farmacodinámicos fundamentales.


Assuntos
Aminoácidos , Receptores Acoplados a Proteínas G , Hormônios , Humanos , Ligantes , Modelos Moleculares
4.
Respiration ; 98(5): 447-454, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31437842

RESUMO

BACKGROUND: Chronic obstructive pulmonary disease (COPD) affects up to 65 million people worldwide, and COPD exacerbation causes tissue damage and subsequent loss of lung function. It is a multifactorial event in which respiratory infections are involved, but little is known about its dynamics. OBJECTIVES: The objective of our study was to determine the microbiome composition during an exacerbation event and post-stabilization. METHODS: We conducted an observational analytical study of a cohort of 55 COPD patients in which 2 sputum samples (the first taken during an exacerbation event and the second during clinical post-stabilization) were submitted to 16s RNA ribosomal analysis by Illumina Miseq Next Generation Sequencing (NGS). The presence of respiratory viruses was also determined. RESULTS: Our study found a stable microbiome composition in the post-stabilization sputum samples of COPD patients, and 4 additional microbiomes in samples taken during the exacerbation, 3 of which showed a marked dysbiosis by Haemophilus, Pseudomonas, and Serratia. The fourth exacerbation microbiome had a very similar composition to post-stabilization samples, but some pathogens such as Moraxella and respiratory viruses were also found. CONCLUSIONS: Our study reveals the main protagonists involved in lung microbiome dynamics during an exacerbation event and post-stabilization in COPD patients by NGS analysis.


Assuntos
Microbiota , Doença Pulmonar Obstrutiva Crônica/microbiologia , Escarro/microbiologia , Idoso , Idoso de 80 Anos ou mais , Progressão da Doença , Feminino , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Masculino , Pessoa de Meia-Idade
5.
Gac Med Mex ; 153(3): 379-382, 2017.
Artigo em Espanhol | MEDLINE | ID: mdl-28763078

RESUMO

El solo nombre del Dr. Ignacio Chávez y la calidad académica de los que me han precedido me hacen sentir emocionado, consciente de que me encuentro sobre los hombros de grandes aportadores a nuestra medicina.


Assuntos
Medicina Molecular/tendências , História do Século XX , Humanos , México , Medicina Molecular/história
6.
Nat Genet ; 38(3): 320-3, 2006 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-16415884

RESUMO

We have previously reported suggestive linkage of type 2 diabetes mellitus to chromosome 10q. We genotyped 228 microsatellite markers in Icelandic individuals with type 2 diabetes and controls throughout a 10.5-Mb interval on 10q. A microsatellite, DG10S478, within intron 3 of the transcription factor 7-like 2 gene (TCF7L2; formerly TCF4) was associated with type 2 diabetes (P = 2.1 x 10(-9)). This was replicated in a Danish cohort (P = 4.8 x 10(-3)) and in a US cohort (P = 3.3 x 10(-9)). Compared with non-carriers, heterozygous and homozygous carriers of the at-risk alleles (38% and 7% of the population, respectively) have relative risks of 1.45 and 2.41. This corresponds to a population attributable risk of 21%. The TCF7L2 gene product is a high mobility group box-containing transcription factor previously implicated in blood glucose homeostasis. It is thought to act through regulation of proglucagon gene expression in enteroendocrine cells via the Wnt signaling pathway.


Assuntos
Diabetes Mellitus Tipo 2/genética , Fatores de Transcrição TCF/genética , Mapeamento Cromossômico , Cromossomos Humanos Par 10 , Estudos de Coortes , Dinamarca , Frequência do Gene , Triagem de Portadores Genéticos , Predisposição Genética para Doença , Humanos , Íntrons , Repetições de Microssatélites , Dados de Sequência Molecular , Valores de Referência , Proteína 2 Semelhante ao Fator 7 de Transcrição
7.
Nat Genet ; 38(1): 68-74, 2006 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-16282974

RESUMO

Variants of the gene ALOX5AP (also known as FLAP) encoding arachidonate 5-lipoxygenase activating protein are known to be associated with risk of myocardial infarction. Here we show that a haplotype (HapK) spanning the LTA4H gene encoding leukotriene A4 hydrolase, a protein in the same biochemical pathway as ALOX5AP, confers modest risk of myocardial infarction in an Icelandic cohort. Measurements of leukotriene B4 (LTB4) production suggest that this risk is mediated through upregulation of the leukotriene pathway. Three cohorts from the United States also show that HapK confers a modest relative risk (1.16) in European Americans, but it confers a threefold larger risk in African Americans. About 27% of the European American controls carried at least one copy of HapK, as compared with only 6% of African American controls. Our analyses indicate that HapK is very rare in Africa and that its occurrence in African Americans is due to European admixture. Interactions with other genetic or environmental risk factors that are more common in African Americans are likely to account for the greater relative risk conferred by HapK in this group.


Assuntos
População Negra/genética , Negro ou Afro-Americano/genética , Epóxido Hidrolases/genética , Predisposição Genética para Doença , Infarto do Miocárdio/genética , População Branca/genética , Estudos de Casos e Controles , Epóxido Hidrolases/metabolismo , Variação Genética , Haplótipos/genética , Humanos , Islândia , Desequilíbrio de Ligação , Dados de Sequência Molecular
8.
Nat Genet ; 38(6): 652-8, 2006 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-16682969

RESUMO

With the increasing incidence of prostate cancer, identifying common genetic variants that confer risk of the disease is important. Here we report such a variant on chromosome 8q24, a region initially identified through a study of Icelandic families. Allele -8 of the microsatellite DG8S737 was associated with prostate cancer in three case-control series of European ancestry from Iceland, Sweden and the US. The estimated odds ratio (OR) of the allele is 1.62 (P = 2.7 x 10(-11)). About 19% of affected men and 13% of the general population carry at least one copy, yielding a population attributable risk (PAR) of approximately 8%. The association was also replicated in an African American case-control group with a similar OR, in which 41% of affected individuals and 30% of the population are carriers. This leads to a greater estimated PAR (16%) that may contribute to higher incidence of prostate cancer in African American men than in men of European ancestry.


Assuntos
População Negra/genética , Neoplasias da Próstata/genética , População Branca/genética , Alelos , Humanos , Masculino , Repetições de Microssatélites/genética , Polimorfismo de Nucleotídeo Único
9.
Int J Neuropsychopharmacol ; 18(4)2014 Oct 31.
Artigo em Inglês | MEDLINE | ID: mdl-25522406

RESUMO

BACKGROUND: Despite the widespread use of antipsychotics, little is known of the molecular bases behind the action of antipsychotic drugs. A genome-wide study is needed to characterize the genes that affect the clinical response and their adverse effects. METHODS: Here we show the analysis of the blood transcriptome of 22 schizophrenia patients before and after medication with atypical antipsychotics by next-generation sequencing. RESULTS: We found that 17 genes, among the 21 495 genes analyzed, have significantly-altered expression after medication (p-value adjusted [Padj] <0.05). Six genes (ADAMTS2, CD177, CNTNAP3, ENTPD2, RFX2, and UNC45B) out of the 17 are among the 200 genes that we characterized with differential expression in a previous study between antipsychotic-naïve schizophrenia patients and controls (Sainz et al., 2013). This number of schizophrenia-altered expression genes is significantly higher than expected by chance (Chi-test, Padj 1.19E-50), suggesting that at least part of the antipsychotic beneficial effects is exerted by modulating the expression of these genes. Interestingly, all six of these genes were overexpressed in patients and reverted to control levels of expression after treatment. We also found a significant enrichment of genes related to obesity and diabetes, known adverse affects of antipsychotics. CONCLUSIONS: These results may facilitate understanding of unknown molecular mechanisms behind schizophrenia symptoms and the molecular mechanisms of antipsychotic drugs.


Assuntos
Antipsicóticos/uso terapêutico , Esquizofrenia/sangue , Esquizofrenia/tratamento farmacológico , Transcriptoma/efeitos dos fármacos , Adulto , Aripiprazol/uso terapêutico , Benzodiazepinas/uso terapêutico , Feminino , Humanos , Estudos Longitudinais , Masculino , Olanzapina , Piperazinas/uso terapêutico , Estudos Prospectivos , Escalas de Graduação Psiquiátrica , Fumarato de Quetiapina/uso terapêutico , Risperidona/uso terapêutico , Tiazóis/uso terapêutico , Resultado do Tratamento
10.
Arthritis Rheum ; 65(1): 197-205, 2013 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-23124911

RESUMO

OBJECTIVE: To determine genome-wide methylation profiles of bone from patients with hip osteoarthritis (OA) and those with osteoporotic (OP) hip fractures. METHODS: Trabecular bone pieces were obtained from the central part of the femoral head of 27 patients with hip fractures and 26 patients with hip OA. DNA was isolated, and methylation was explored with Illumina methylation arrays. RNA was extracted, pooled, and deep-sequenced to obtain the whole transcriptome. Differentially methylated regions were identified, and connections between genes with differentially methylated regions were explored by pathway and text-mining analyses. RESULTS: After quality control, methylation of 23,367 CpG sites (13,463 genes) was analyzed. There was a genome-wide inverse relationship between methylation and gene expression in both patient groups. Comparison of OP and OA bones revealed 241 CpG sites, located in 228 genes, with significant differences in methylation (false discovery rate<0.05). Of them, 217 were less methylated in OP than in OA. The absolute methylation differences were >5% in 128 CpG sites and >10% in 45 CpG sites. The differentially methylated genes were enriched for association with bone traits in the genome-wide association study catalog. Pathway analysis and text-mining analysis with Gene Relationships Across Implicated Loci software revealed enrichment in genes participating in glycoprotein metabolism or cell differentiation, and particularly in the homeobox superfamily of transcription factors. CONCLUSION: Genome-wide methylation profiling of bone samples revealed differentially methylated regions in OP and OA. These regions were enriched in genes associated with cell differentiation and skeletal embryogenesis, such as those in the homeobox superfamily, suggesting the existence of a developmental component in the predisposition to these disorders.


Assuntos
Osso e Ossos/metabolismo , Metilação de DNA , Osteoartrite do Quadril/genética , Osteoporose/genética , Fraturas por Osteoporose/genética , Idoso , Idoso de 80 Anos ou mais , Feminino , Perfilação da Expressão Gênica , Estudo de Associação Genômica Ampla , Humanos , Pessoa de Meia-Idade , Dados de Sequência Molecular , Osteoartrite do Quadril/metabolismo , Osteoporose/metabolismo , Fraturas por Osteoporose/metabolismo , Reação em Cadeia da Polimerase em Tempo Real , Análise de Sequência de DNA
11.
Nat Genet ; 37(2): 129-37, 2005 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-15654335

RESUMO

A refined physical map of chromosome 17q21.31 uncovered a 900-kb inversion polymorphism. Chromosomes with the inverted segment in different orientations represent two distinct lineages, H1 and H2, that have diverged for as much as 3 million years and show no evidence of having recombined. The H2 lineage is rare in Africans, almost absent in East Asians but found at a frequency of 20% in Europeans, in whom the haplotype structure is indicative of a history of positive selection. Here we show that the H2 lineage is undergoing positive selection in the Icelandic population, such that carrier females have more children and have higher recombination rates than noncarriers.


Assuntos
Inversão Cromossômica , Cromossomos Humanos Par 17 , Seleção Genética , População Branca/genética , Feminino , Frequência do Gene , Haplótipos , Humanos , Islândia , Dados de Sequência Molecular , Filogenia , Mapeamento Físico do Cromossomo , Polimorfismo Genético , Recombinação Genética
12.
Spectrochim Acta A Mol Biomol Spectrosc ; 322: 124823, 2024 Dec 05.
Artigo em Inglês | MEDLINE | ID: mdl-39033609

RESUMO

In the present work, we study different physicochemical properties related to LADME processes of volasertib, a Polo-like kinase 1 inhibitor in advanced clinical trials. Firstly, the protonation equilibria, the extent of ionization at the physiological pH and pKa values of this drug are studied combining spectroscopic techniques and computational calculations. Secondly, the binding process of volasertib to the human serum albumin (HSA) protein is analyzed by fluorescence spectroscopy. We report a high binding constant to HSA (Ka = 4.10 × 106 M-1) and their pharmacokinetic implications are discussed accordingly. The negative enthalpy and entropy (ΔH0 = -54.49 kJ/mol; ΔS0 = -58.90 J K-1 mol-1) determined for the binding process suggests the implication of hydrogen bonds and van der Waals interactions in the formation of the HSA-volasertib complex. Additionally, volasertib is encapsulated in an alginate/montmorillonite bionanocomposite as a proof of concept for an oral delivery nanocarrier. The physical properties of that nanocomposite as well as volasertib delivery kinetics are analyzed.


Assuntos
Alginatos , Bentonita , Nanocompostos , Espectrometria de Fluorescência , Humanos , Alginatos/química , Bentonita/química , Ligação de Hidrogênio , Concentração de Íons de Hidrogênio , Nanocompostos/química , Ligação Proteica , Pteridinas/química , Albumina Sérica Humana/química , Albumina Sérica Humana/metabolismo , Termodinâmica
13.
Nat Genet ; 31(3): 241-7, 2002 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-12053178

RESUMO

Determination of recombination rates across the human genome has been constrained by the limited resolution and accuracy of existing genetic maps and the draft genome sequence. We have genotyped 5,136 microsatellite markers for 146 families, with a total of 1,257 meiotic events, to build a high-resolution genetic map meant to: (i) improve the genetic order of polymorphic markers; (ii) improve the precision of estimates of genetic distances; (iii) correct portions of the sequence assembly and SNP map of the human genome; and (iv) build a map of recombination rates. Recombination rates are significantly correlated with both cytogenetic structures (staining intensity of G bands) and sequence (GC content, CpG motifs and poly(A)/poly(T) stretches). Maternal and paternal chromosomes show many differences in locations of recombination maxima. We detected systematic differences in recombination rates between mothers and between gametes from the same mother, suggesting that there is some underlying component determined by both genetic and environmental factors that affects maternal recombination rates.


Assuntos
Mapeamento Cromossômico , Genoma Humano , Repetições de Microssatélites/genética , Recombinação Genética/genética , Sequência de Bases , Bandeamento Cromossômico , Genótipo , Humanos , Meiose , Linhagem , Polimorfismo de Nucleotídeo Único , Análise de Regressão
14.
Nat Genet ; 36(3): 233-9, 2004 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-14770184

RESUMO

We mapped a gene predisposing to myocardial infarction to a locus on chromosome 13q12-13. A four-marker single-nucleotide polymorphism (SNP) haplotype in this locus spanning the gene ALOX5AP encoding 5-lipoxygenase activating protein (FLAP) is associated with a two times greater risk of myocardial infarction in Iceland. This haplotype also confers almost two times greater risk of stroke. Another ALOX5AP haplotype is associated with myocardial infarction in individuals from the UK. Stimulated neutrophils from individuals with myocardial infarction produce more leukotriene B4, a key product in the 5-lipoxygenase pathway, than do neutrophils from controls, and this difference is largely attributed to cells from males who carry the at-risk haplotype. We conclude that variants of ALOX5AP are involved in the pathogenesis of both myocardial infarction and stroke by increasing leukotriene production and inflammation in the arterial wall.


Assuntos
Proteínas de Transporte/genética , Proteínas de Membrana/genética , Infarto do Miocárdio/genética , Acidente Vascular Cerebral/genética , Proteínas Ativadoras de 5-Lipoxigenase , Mapeamento Cromossômico , Cromossomos Humanos Par 13 , Predisposição Genética para Doença , Humanos , Leucotrieno B4/sangue , Repetições de Microssatélites , Polimorfismo de Nucleotídeo Único
15.
Mol Cell Endocrinol ; 570: 111930, 2023 06 15.
Artigo em Inglês | MEDLINE | ID: mdl-37054840

RESUMO

LPA1 internalization to endosomes was studied employing Förster Resonance Energy Transfer (FRET) in cells coexpressing the mCherry-lysophosphatidic acid LPA1 receptors and distinct eGFP-tagged Rab proteins. Lysophosphatidic acid (LPA)-induced internalization was rapid and decreased afterward: phorbol myristate acetate (PMA) action was slower and sustained. LPA stimulated LPA1-Rab5 interaction rapidly but transiently, whereas PMA action was rapid but sustained. Expression of a Rab5 dominant-negative mutant blocked LPA1-Rab5 interaction and receptor internalization. LPA-induced LPA1-Rab9 interaction was only observed at 60 min, and LPA1-Rab7 interaction after 5 min with LPA and after 60 min with PMA. LPA triggered immediate but transient rapid recycling (i.e., LPA1-Rab4 interaction), whereas PMA action was slower but sustained. Agonist-induced slow recycling (LPA1-Rab11 interaction) increased at 15 min and remained at this level, whereas PMA action showed early and late peaks. Our results indicate that LPA1 receptor internalization varies with the stimuli.


Assuntos
Transferência Ressonante de Energia de Fluorescência , Receptores de Ácidos Lisofosfatídicos , Receptores de Ácidos Lisofosfatídicos/metabolismo , Fosforilação , Acetato de Tetradecanoilforbol/farmacologia , Endossomos/metabolismo , Lisofosfolipídeos/farmacologia , Lisofosfolipídeos/metabolismo
16.
Microorganisms ; 11(9)2023 Aug 31.
Artigo em Inglês | MEDLINE | ID: mdl-37764052

RESUMO

This study aimed to evaluate if the change of vehicle for CTZ (Chloramphenicol, Tetracycline, zinc oxide, and Eugenol) paste improves the inhibition of Enterococcus faecalis in vitro. The vehicles evaluated alone and mixed with CTZ were Eugenol, propylene glycol (PG), super-oxidized solution (SOS), grapefruit-seed extract (GSE), and 0.9% saline solution as a negative control. A clinical isolate of E. faecalis was morphologically and biochemically characterized, and its antimicrobial susceptibility was tested using 20 antimicrobial agents. Once characterized, the clinical isolate was cultivated to perform the Kirby-Bauer disc diffusion method with paper discs embedded with the different vehicles mixed or used alone, and incubated at 37 °C for 24 h. Data were analyzed using one-way ANOVA, and the means were compared using Tukey test with a significance level of p < 0.05. For vehicles used alone, GSE presented the greatest inhibition showing a statistically significant difference with the rest of the vehicles. When vehicles were mixed with the CTZ paste, PG showed a greater inhibition with a statistically significant difference from the rest of the vehicles. In conclusion, the vehicle used to mix the CTZ paste plays an important role in the inhibition of E. faecalis in vitro; therefore, we consider that this can be an important factor to achieve success in the use of this technique.

17.
J Photochem Photobiol B ; 232: 112477, 2022 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-35644070

RESUMO

In the present work, the interactions of the novel kinase inhibitors BI-2536, Volasetib (BI-6727) and Ro-3280 with the pharmacological target PLK1 have been studied by fluorescence spectroscopy and molecular dynamics calculations. High Stern-Volmer constants were found in fluorescence experiments suggesting the formation of stable protein-ligand complexes. In addition, it was observed that the binding constant between BI-2536 and PLK1 increases about 100-fold in presence of the phosphopeptide Cdc25C-p that docks to the polo box domain of the protein and releases the kinase domain. All the determined binding constants are higher for the kinase inhibitors than for their competitor for the active center (ATP) being BI-2536 and Volasertib the inhibitors that showed more affinity for PLK1. Calculated binding free energies confirmed the higher affinity of PLK1 for BI-2536 and Volasertib than for ATP. The higher affinity of the inhibitors to PLK1 compared to ATP was mainly attributed to stronger van der Waals interactions. Results may help with the challenge of designing and developing new kinase inhibitors more effective in clinical cancer therapy.


Assuntos
Proteínas de Ciclo Celular , Proteínas Serina-Treonina Quinases , Trifosfato de Adenosina , Proteínas de Ciclo Celular/metabolismo , Inibidores de Proteínas Quinases/química , Proteínas Proto-Oncogênicas/metabolismo , Pteridinas
18.
BMC Med ; 9: 13, 2011 Feb 03.
Artigo em Inglês | MEDLINE | ID: mdl-21291539

RESUMO

The hunt for the genetic contributors to complex disease has used a number of strategies, resulting in the identification of variants associated with many of the common diseases affecting society. However most of the genetic variants detected to date are single nucleotide polymorphisms (SNPs) and copy number variants (CNVs) and fall far short of explaining the full genetic component of any given disease. An as yet untapped genomic mechanism is somatic gene conversion and deletion, which could be complicit in disease risk but has been challenging to detect in genome-wide datasets. In a recent publication in BMC Medicine by Kenneth Ross, the author uses existing datasets to look at somatic gene conversion and deletion in human disease. Here, we describe how Ross's recent efforts to detect such occurrences could impact the field going forward.


Assuntos
Conversão Gênica/genética , Genética Populacional , Estudo de Associação Genômica Ampla/métodos , Bases de Dados de Ácidos Nucleicos , Genótipo , Humanos , Polimorfismo de Nucleotídeo Único/genética
19.
Front Pharmacol ; 12: 646701, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33762960

RESUMO

Background: Antipsychotics modulate expression of inflammatory cytokines and inducible inflammatory enzymes. Elopiprazole (a phenylpiperazine antipsychotic drug in phase 1) has been characterized as a therapeutic drug to treat SARS-CoV-2 infection in a repurposing study. We aim to investigate the potential effects of aripiprazole (an FDA approved phenylpiperazine) on COVID-19-related immunological parameters. Methods: Differential gene expression profiles of non-COVID-19 vs. COVID-19 RNA-Seq samples (CRA002390 project in GSA database) and drug-naïve patients with non-affective psychosis at baseline and after three months of aripiprazole treatment were identified. An integrative transcriptomic analyses of aripiprazole effects on differentially expressed genes in COVID-19 patients was performed. Findings: 82 out the 377 genes (21.7%) with expression significantly altered by aripiprazole have also their expression altered in COVID-19 patients and in 93.9% of these genes their expression is reverted by aripiprazole. The number of common genes with expression altered in both analyses is significantly higher than expected (Fisher's Exact Test, two tail; p value = 3.2e-11). 11 KEGG pathways were significantly enriched with genes with altered expression both in COVID-19 patients and aripiprazole medicated non-affective psychosis patients (p adj<0.05). The most significant pathways were associated to immune responses and mechanisms of hyperinflammation-driven pathology (i.e.,"inflammatory bowel disease (IBD)" (the most significant pathway with a p adj of 0.00021), "Th1 and Th2 cell differentiation" and "B cell receptor signaling pathway") that have been also associated with COVID19 clinical outcome. Interpretation: This exploratory investigation may provide further support to the notion that a protective effect is exerted by aripiprazole (phenylpiperazine) by modulating the expression of genes that have shown to be altered in COVID-19 patients. Along with many ongoing studies and clinical trials, repurposing available medications could be of use in countering SARS-CoV-2 infection, but require further studies and trials.

20.
NPJ Schizophr ; 5(1): 7, 2019 Apr 10.
Artigo em Inglês | MEDLINE | ID: mdl-30971689

RESUMO

Antipsychotic drugs are one of the largest types of prescribed drugs. However, antipsychotic-induced weight gain (AIWG) is a major problem for the patients. AIWG increases cardiovascular and cerebrovascular morbidity and mortality, and reduces quality of life and drug compliance. To characterize changes in gene expression related to AIWG, we sequenced total messenger RNA from the blood samples of two groups of schizophrenia patients before and after 3 months of treatment with antipsychotics. The "weight gain" group was defined by an increase of body mass index (BMI) >1.5 points (18 patients; median BMI increase = 2.69) and the "no weight gain" group was defined by a change of BMI between <1.0 and >-1.0 points (18 patients; median BMI increase = 0.26). We found 115 genes with significant differential expression in the weight gain group before and after medication and 156 in the no weight gain group before and after medication. The weight gain group was significantly enriched with genes related to "obesity" and "BMI" (Fisher; p = 0.0002 and 0.01, respectively) according to the Gene Reference into Function (GeneRIF) database. In the no weight gain group, the enrichment was much smaller (Fisher; p = 0.02 and 0.79). This study is a first step toward detecting genetic factors that cause AIWG and to generating prediction tests in future studies with larger data sets.

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