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1.
Cell ; 178(6): 1299-1312.e29, 2019 09 05.
Artículo en Inglés | MEDLINE | ID: mdl-31474368

RESUMEN

Metformin is the first-line therapy for treating type 2 diabetes and a promising anti-aging drug. We set out to address the fundamental question of how gut microbes and nutrition, key regulators of host physiology, affect the effects of metformin. Combining two tractable genetic models, the bacterium E. coli and the nematode C. elegans, we developed a high-throughput four-way screen to define the underlying host-microbe-drug-nutrient interactions. We show that microbes integrate cues from metformin and the diet through the phosphotransferase signaling pathway that converges on the transcriptional regulator Crp. A detailed experimental characterization of metformin effects downstream of Crp in combination with metabolic modeling of the microbiota in metformin-treated type 2 diabetic patients predicts the production of microbial agmatine, a regulator of metformin effects on host lipid metabolism and lifespan. Our high-throughput screening platform paves the way for identifying exploitable drug-nutrient-microbiome interactions to improve host health and longevity through targeted microbiome therapies. VIDEO ABSTRACT.


Asunto(s)
Diabetes Mellitus Tipo 2/tratamiento farmacológico , Microbioma Gastrointestinal/efectos de los fármacos , Interacciones Microbiota-Huesped/efectos de los fármacos , Hipoglucemiantes/uso terapéutico , Metformina/uso terapéutico , Agmatina/metabolismo , Animales , Caenorhabditis elegans/microbiología , Proteína Receptora de AMP Cíclico , Escherichia coli/efectos de los fármacos , Escherichia coli/genética , Humanos , Hipoglucemiantes/farmacología , Metabolismo de los Lípidos/efectos de los fármacos , Longevidad/efectos de los fármacos , Metformina/farmacología , Nutrientes/metabolismo
2.
Cell ; 169(3): 442-456.e18, 2017 04 20.
Artículo en Inglés | MEDLINE | ID: mdl-28431245

RESUMEN

Fluoropyrimidines are the first-line treatment for colorectal cancer, but their efficacy is highly variable between patients. We queried whether gut microbes, a known source of inter-individual variability, impacted drug efficacy. Combining two tractable genetic models, the bacterium E. coli and the nematode C. elegans, we performed three-way high-throughput screens that unraveled the complexity underlying host-microbe-drug interactions. We report that microbes can bolster or suppress the effects of fluoropyrimidines through metabolic drug interconversion involving bacterial vitamin B6, B9, and ribonucleotide metabolism. Also, disturbances in bacterial deoxynucleotide pools amplify 5-FU-induced autophagy and cell death in host cells, an effect regulated by the nucleoside diphosphate kinase ndk-1. Our data suggest a two-way bacterial mediation of fluoropyrimidine effects on host metabolism, which contributes to drug efficacy. These findings highlight the potential therapeutic power of manipulating intestinal microbiota to ensure host metabolic health and treat disease.


Asunto(s)
Antineoplásicos/metabolismo , Escherichia coli/metabolismo , Fluorouracilo/metabolismo , Microbioma Gastrointestinal , Animales , Autofagia , Caenorhabditis elegans , Muerte Celular , Neoplasias Colorrectales/tratamiento farmacológico , Dieta , Escherichia coli/enzimología , Escherichia coli/genética , Humanos , Modelos Animales , Pentosiltransferasa/genética
3.
J Chem Inf Model ; 64(15): 5817-5831, 2024 Aug 12.
Artículo en Inglés | MEDLINE | ID: mdl-39037942

RESUMEN

We propose HydraScreen, a deep-learning framework for safe and robust accelerated drug discovery. HydraScreen utilizes a state-of-the-art 3D convolutional neural network designed for the effective representation of molecular structures and interactions in protein-ligand binding. We designed an end-to-end pipeline for high-throughput screening and lead optimization, targeting applications in structure-based drug design. We assessed our approach using established public benchmarks based on the CASF-2016 core set, achieving top-tier results in affinity and pose prediction (Pearson's r = 0.86, RMSE = 1.15, Top-1 = 0.95). We introduced a novel approach for interaction profiling, aimed at detecting potential biases within both the model and data sets. This approach not only enhanced interpretability but also reinforced the impartiality of our methodology. Finally, we demonstrated HydraScreen's ability to generalize effectively across novel proteins and ligands through a temporal split. We also provide insights into potential avenues for future development aimed at enhancing the robustness of machine learning scoring functions. HydraScreen (accessible at http://hydrascreen.ro5.ai/paper) provides a user-friendly GUI and a public API, facilitating the easy-access assessment of protein-ligand complexes.


Asunto(s)
Aprendizaje Profundo , Descubrimiento de Drogas , Descubrimiento de Drogas/métodos , Ligandos , Proteínas/química , Proteínas/metabolismo , Unión Proteica , Redes Neurales de la Computación , Diseño de Fármacos
4.
PLoS Genet ; 16(11): e1009083, 2020 11.
Artículo en Inglés | MEDLINE | ID: mdl-33253201

RESUMEN

Increased cellular degradation by autophagy is a feature of many interventions that delay ageing. We report here that increased autophagy is necessary for reduced insulin-like signalling (IIS) to extend lifespan in Drosophila and is sufficient on its own to increase lifespan. We first established that the well-characterised lifespan extension associated with deletion of the insulin receptor substrate chico was completely abrogated by downregulation of the essential autophagy gene Atg5. We next directly induced autophagy by over-expressing the major autophagy kinase Atg1 and found that a mild increase in autophagy extended lifespan. Interestingly, strong Atg1 up-regulation was detrimental to lifespan. Transcriptomic and metabolomic approaches identified specific signatures mediated by varying levels of autophagy in flies. Transcriptional upregulation of mitochondrial-related genes was the signature most specifically associated with mild Atg1 upregulation and extended lifespan, whereas short-lived flies, possessing strong Atg1 overexpression, showed reduced mitochondrial metabolism and up-regulated immune system pathways. Increased proteasomal activity and reduced triacylglycerol levels were features shared by both moderate and high Atg1 overexpression conditions. These contrasting effects of autophagy on ageing and differential metabolic profiles highlight the importance of fine-tuning autophagy levels to achieve optimal healthspan and disease prevention.


Asunto(s)
Autofagia/genética , Longevidad/genética , Mitocondrias/genética , Envejecimiento/genética , Animales , Homólogo de la Proteína 1 Relacionada con la Autofagia/genética , Homólogo de la Proteína 1 Relacionada con la Autofagia/metabolismo , Proteínas de Drosophila/genética , Proteínas de Drosophila/metabolismo , Drosophila melanogaster/genética , Expresión Génica/genética , Regulación de la Expresión Génica/genética , Genes Mitocondriales/genética , Proteínas Sustrato del Receptor de Insulina/genética , Proteínas Sustrato del Receptor de Insulina/metabolismo , Proteínas Serina-Treonina Quinasas/genética , Receptor de Insulina/genética , Transducción de Señal
5.
Am Nat ; 180(3): 388-93, 2012 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-22854081

RESUMEN

Many classic models of speciation incorporate assortative mating based on mating groups, such as plants with different flowering times, and they investigate whether an ecological trait under disruptive natural selection becomes genetically associated with the selectively neutral mating trait. It is well known that this genetic association is potently destroyed by recombination. In this note, we point out a more fundamental difficulty: if a "knife-edge" symmetry assumption of previous models is violated, then the mating trait is no longer neutral and sexual selection eliminates the polymorphism in the mating locus. This result strengthens the growing consensus that magic traits are the more likely route to nonallopatric speciation. We expand the model assuming also ecological selection on the mating trait and investigate the conditions for natural selection to overcome sexual selection and maintain mating polymorphism; we find that the combination of natural and sexual selection can cause also bistability of allele frequencies.


Asunto(s)
Especiación Genética , Magnoliopsida/genética , Preferencia en el Apareamiento Animal , Modelos Biológicos , Selección Genética , Animales , Femenino , Masculino
6.
Eur J Cancer Prev ; 25(1): 77-84, 2016 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-25714784

RESUMEN

NSAIDs have been observed to have cancer-preventive properties, but the actual mechanism is elusive. We hypothesize that NSAIDs might have an effect through common pathways and targets of anticancer drugs by exploiting promiscuities of anticancer drug targets. Here, we have explored NSAIDs by their structural and pharmacophoric similarities with small anticancer molecules. In-silico analyses have shown a strong similarity between NSAIDs and protein kinase (PK) inhibitors. The calculated affinities of NSAIDs were found to be lower than the affinities of anticancer drugs, but higher than the affinities of compounds that are not specific to PKs. The competitive inhibition model suggests that PK might be inhibited by around 10%, which was confirmed by biochemical screening of some NSAIDs against PKs. NSAIDs did not affect all PKs universally, but had specificities for certain sets of PKs, which differed according to the NSAID. The study revealed potentially new features and mechanisms of NSAIDs that are useful in explaining their role in cancer prevention, which might lead to clinically significant breakthroughs in the future.


Asunto(s)
Antiinflamatorios no Esteroideos/farmacología , Antineoplásicos/farmacología , Neoplasias/enzimología , Neoplasias/prevención & control , Inhibidores de Proteínas Quinasas/farmacología , Proteínas Quinasas/química , Unión Competitiva , Humanos
7.
Biophys Chem ; 205: 51-65, 2015 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-26079542

RESUMEN

Para substituted tetrafluorobenzenesulfonamides bind to carbonic anhydrases (CAs) extremely tightly and exhibit some of the strongest known protein-small ligand interactions, reaching an intrinsic affinity of 2 pM as determined by displacement isothermal titration calorimetry (ITC). The enthalpy and entropy of binding to five CA isoforms were measured by ITC in two buffers of different protonation enthalpies. The pKa values of compound sulfonamide groups were measured potentiometrically and spectrophotometrically, and enthalpies of protonation were measured by ITC in order to evaluate the proton linkage contributions to the observed binding thermodynamics. Intrinsic means the affinity of a sulfonamide anion for the Zn bound water form of CAs. Fluorination of the benzene ring significantly enhanced the observed affinities as it increased the fraction of deprotonated ligand while having little impact on intrinsic affinities. Intrinsic enthalpy contributions to the binding affinity were dominant over entropy and were more exothermic for CA I than for other CA isoforms. Thermodynamic measurements together with the X-ray crystallographic structures of protein-ligand complexes enabled analysis of structure-activity relationships in this enzyme ligand system.


Asunto(s)
Anhidrasas Carbónicas/metabolismo , Entropía , Sulfonamidas/química , Sulfonamidas/metabolismo , Calorimetría , Anhidrasas Carbónicas/química , Halogenación , Humanos , Isoenzimas/química , Isoenzimas/metabolismo , Isomerismo , Modelos Moleculares , Unión Proteica , Conformación Proteica , Protones , Agua/química , Zinc/química , Bencenosulfonamidas
8.
J Pharm Sci ; 103(7): 2147-2156, 2014 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-24801583

RESUMEN

Although drug delivery with nanovectors is regarded as one of the paradigm-shifting advances in modern medicine, the compatibility and performance of drug-vector formulations have not been systematically studied in terms of their physicochemistry and pharmacokinetics (PKs). The drug delivery systems (DDSs), currently available in clinics or trials, were analyzed based on hydrophobicity and anatomical therapeutic chemical (ATC) classification of drug payloads. Four major types of DDSs differentiated based on DDS structure and drug hydrophobicity, where payload hydrophobicity decreased: micelles, serum albumin, liposome membrane, and liposome interior. A strong relationship between the increase in half-life in DDS formulation and drug hydrophobicity was found with up to 200-fold greater increase for hydrophilic drugs. The analysis results seemingly integrated PKs, ATC, and hydrophobicity to reinforce the development or optimization of drug delivery vectors and their formulations.


Asunto(s)
Portadores de Fármacos/química , Nanopartículas/química , Preparaciones Farmacéuticas , Farmacocinética , Fenómenos Químicos , Interpretación Estadística de Datos , Bases de Datos Farmacéuticas , Liberación de Fármacos , Interacciones Hidrofóbicas e Hidrofílicas , Liposomas , Micelas , Tamaño de la Partícula , Preparaciones Farmacéuticas/administración & dosificación , Preparaciones Farmacéuticas/química , Preparaciones Farmacéuticas/metabolismo , Unión Proteica , Albúmina Sérica/química , Albúmina Sérica/metabolismo
9.
J Med Chem ; 57(22): 9435-46, 2014 Nov 26.
Artículo en Inglés | MEDLINE | ID: mdl-25358084

RESUMEN

Human carbonic anhydrase IX (CA IX) is highly expressed in tumor tissues, and its selective inhibition provides a potential target for the treatment of numerous cancers. Development of potent, highly selective inhibitors against this target remains an unmet need in anticancer therapeutics. A series of fluorinated benzenesulfonamides with substituents on the benzene ring was designed and synthesized. Several of these exhibited a highly potent and selective inhibition profile against CA IX. Three fluorine atoms significantly increased the affinity by withdrawing electrons and lowering the pKa of the benzenesulfonamide group. The bulky ortho substituents, such as cyclooctyl or even cyclododecyl groups, fit into the hydrophobic pocket in the active site of CA IX but not CA II, as shown by the compound's co-crystal structure with chimeric CA IX. The strongest inhibitor of recombinant human CA IX's catalytic domain in human cells achieved an affinity of 50 pM. However, the high affinity diminished the selectivity. The most selective compound for CA IX exhibited 10 nM affinity. The compound that showed the best balance between affinity and selectivity bound with 1 nM affinity. The inhibitors described in this work provide the basis for novel anticancer therapeutics targeting CA IX.


Asunto(s)
Inhibidores de Anhidrasa Carbónica/química , Anhidrasas Carbónicas/química , Diseño de Fármacos , Benceno/química , Calorimetría , Dióxido de Carbono/química , Anhidrasa Carbónica IV/química , Catálisis , Dominio Catalítico , Cristalización , Cristalografía por Rayos X , Humanos , Concentración de Iones de Hidrógeno , Cinética , Neoplasias/tratamiento farmacológico , Unión Proteica , Conformación Proteica , Proteínas Recombinantes/química , Sulfonamidas/química , Termodinámica
10.
J Phys Chem B ; 116(7): 2138-44, 2012 Feb 23.
Artículo en Inglés | MEDLINE | ID: mdl-22268667

RESUMEN

The interaction between positively and negatively charged linear surfactants is an interesting system for the understanding of the fundamental interplay of hydrophobic and ionic forces in lipid membranes and proteins. We used isothermal titration calorimetry to dissect the Gibbs free energies, enthalpies, entropies, and heat capacities of interaction into hydrophobic and ionic contributions for alkylamine interaction with alkyl sulfates and alkane sulfonates. Dependence on aliphatic chain length, surfactant concentration, temperature, and ionic strength provided a detailed thermodynamic description of this interaction. Reactions of surfactants with tails longer than approximately 10 carbon atoms were primarily driven by enthalpy changes arising from solid-phase interactions between aliphatic tails. Entropic contributions were small relative to enthalpic ones. Contributions of methylene groups were additive. The binding reaction can yield a solid or liquid complex, depending on temperature. Thermodynamic dissection yielded the parameters of the phase transition.


Asunto(s)
Cationes/química , Tensoactivos/química , Alcanosulfonatos/química , Aminas/química , Calorimetría , Sulfatos/química , Temperatura , Termodinámica , Volumetría
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