RESUMEN
Recurrent pericarditis (RP) has been traditionally regarded as a "nightmare" for both clinicians and patients. Until approximately a decade ago, available treatments were thin on the ground with non-steroidal anti-inflammatory medications, glucocorticoids, colchicine, and classical immunosuppressants being the only options. The first important step in the tale of RP was the advent of colchicine in clinical practice, which has been shown to halve the rate of first and subsequent pericarditis recurrences. The second major breakthrough advance in this setting was the introduction of interleukin-1 inhibitors based on the recently unveiled autoinflammatory nature of pericarditis. At present, anti-interleukin-1 inhibitors available for clinical use in patients with refractory RP include anakinra and rilonacept, with the latter having obtained FDA approval for this indication. Apart from the remarkable efficacy and good safety profile which is a common feature of all anti-interleukin-1 compounds, rilonacept has the advantage of weekly administration (instead of daily compared to anakinra) which is important in terms of adherence to treatment and improved quality of life albeit at the expense of a higher cost. This review aims to summarize the available evidence on the role of rilonacept in the treatment of RP and the reduction of the recurrences risk.
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Pericarditis , Proteínas Recombinantes de Fusión , Recurrencia , Humanos , Pericarditis/tratamiento farmacológico , Proteínas Recombinantes de Fusión/uso terapéutico , Proteínas Recombinantes de Fusión/farmacología , Proteínas Recombinantes de Fusión/administración & dosificación , Diseño de Fármacos , Desarrollo de Medicamentos , Interleucina-1/antagonistas & inhibidores , Interleucina-1/metabolismoRESUMEN
Knowledge of protein-ligand complexes is essential for efficient drug design. Virtual docking can bring important information on putative complexes but it is still far from being simultaneously fast and accurate. Receptors are flexible and adapt to the incoming small molecules while docking is highly sensitive to small conformational deviations. Conformation ensemble is providing a mean to simulate protein flexibility. However, modeling multiple protein structures for many targets is seldom connected to ligand screening in an efficient and straightforward manner. @TOME-3 is an updated version of our former pipeline @TOME-2, in which protein structure modeling is now directly interfaced with flexible ligand docking. Sequence-sequence profile comparisons identify suitable PDB templates for structure modeling and ligands from these templates are used to deduce binding sites to be screened. In addition, bound ligand can be used as pharmacophoric restraint during the virtual docking. The latter is performed by PLANTS while the docking poses are analysed through multiple chemoinformatics functions. This unique combination of tools allows rapid and efficient ligand docking on multiple receptor conformations in parallel. @TOME-3 is freely available on the web at https://atome.cbs.cnrs.fr.
Asunto(s)
Simulación del Acoplamiento Molecular , Conformación Proteica , Proteínas , Ligandos , Proteínas/química , Proteínas/metabolismo , Sitios de Unión , Unión Proteica , Programas Informáticos , Diseño de Fármacos , Modelos MolecularesRESUMEN
BACKGROUND: The increasing prevalence of diabetes and the side effects associated with current medications necessitate the development of novel candidate drugs targeting alpha-glucosidase as a potential treatment option. METHODS: This study employed computer-aided drug design techniques to identify potential alpha-glucosidase inhibitors from the PubChem database. Molecular docking was used to evaluate 81,197 compounds, narrowing the set for further analysis and providing insights into ligand-target interactions. An ADMET study assessed the pharmacokinetic properties of these compounds, including absorption, distribution, metabolism, excretion, and toxicity. Molecular dynamics simulations validated the docking results. RESULTS: 9 compounds were identified as potential candidate drugs based on their ability to form stable complexes with alpha-glucosidase and their favorable pharmacokinetic profiles, three of these compounds were subjected to the molecular dynamics, which showed stability throughout the entire 100 ns simulation. CONCLUSION: These findings suggest promising new alpha-glucosidase inhibitors for diabetes treatment. Further validation through in vitro and in vivo studies is recommended to confirm their efficacy and safety.
Asunto(s)
Inhibidores de Glicósido Hidrolasas , Simulación del Acoplamiento Molecular , Simulación de Dinámica Molecular , Triazoles , alfa-Glucosidasas , Inhibidores de Glicósido Hidrolasas/farmacología , Inhibidores de Glicósido Hidrolasas/química , Triazoles/química , Triazoles/farmacología , alfa-Glucosidasas/metabolismo , alfa-Glucosidasas/química , Humanos , Simulación por Computador , Diseño de FármacosRESUMEN
The advent of COVID-19 has brought the use of computer tools to the fore in health research. In recent years, computational methods have proven to be highly effective in a variety of areas, including genomic surveillance, host range prediction, drug target identification, and vaccine development. They were also instrumental in identifying new antiviral compounds and repurposing existing therapeutics to treat COVID-19. Using computational approaches, researchers have made significant advances in understanding the molecular mechanisms of COVID-19 and have developed several promising drug candidates and vaccines. This chapter highlights the critical importance of computational drug design strategies in elucidating various aspects of COVID-19 and their contribution to advancing global drug design efforts during the pandemic. Ultimately, the use of computing tools will continue to play an essential role in health research, enabling researchers to develop innovative solutions to combat new and emerging diseases.
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Antivirales , Tratamiento Farmacológico de COVID-19 , COVID-19 , Biología Computacional , Diseño de Fármacos , SARS-CoV-2 , Humanos , Antivirales/uso terapéutico , Antivirales/farmacología , COVID-19/virología , COVID-19/epidemiología , SARS-CoV-2/efectos de los fármacos , Biología Computacional/métodos , Pandemias , Reposicionamiento de Medicamentos/métodos , Vacunas contra la COVID-19/uso terapéutico , Vacunas contra la COVID-19/inmunologíaRESUMEN
Generative deep learning models enable data-driven de novo design of molecules with tailored features. Chemical language models (CLM) trained on string representations of molecules such as SMILES have been successfully employed to design new chemical entities with experimentally confirmed activity on intended targets. Here, we probe the application of CLM to generate multi-target ligands for designed polypharmacology. We capitalize on the ability of CLM to learn from small fine-tuning sets of molecules and successfully bias the model towards designing drug-like molecules with similarity to known ligands of target pairs of interest. Designs obtained from CLM after pooled fine-tuning are predicted active on both proteins of interest and comprise pharmacophore elements of ligands for both targets in one molecule. Synthesis and testing of twelve computationally favored CLM designs for six target pairs reveals modulation of at least one intended protein by all selected designs with up to double-digit nanomolar potency and confirms seven compounds as designed dual ligands. These results corroborate CLM for multi-target de novo design as source of innovation in drug discovery.
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Aprendizaje Profundo , Diseño de Fármacos , Ligandos , Descubrimiento de Drogas/métodos , Humanos , Modelos Químicos , Polifarmacología , Proteínas/química , Proteínas/metabolismoRESUMEN
Schistosomiasis, also known as bilharzia or snail fever, is a tropical parasitic disease resulting from flatworms of the Schistosoma genus. This often overlooked disease has significant impacts in affected regions, causing enduring morbidity, hindering child development, reducing productivity, and creating economic burdens. Praziquantel (PZQ) is currently the only treatment option for schistosomiasis. Given the potential rise of drug resistance and the limited treatment choices available, there is a need to develop more effective inhibitors for this neglected tropical disease (NTD). In view of this, quantitative structure-activity relationship studies (QSAR), molecular docking, molecular dynamics simulations, drug-likeness, and ADMET predictions were applied to 31 inhibitors of Schistosoma mansoni Dihydroorotate dehydrogenase (SmDHODH). The designed QSAR model demonstrated robust statistical parameters including an R2 of 0.911, R2adj of 0.890, Q2cv of 0.686, R2pred of 0.807, and cR2p of 0.825, confirming its robustness. Compound 26, identified as the most active derivative, emerged as a lead candidate for new potential inhibitors through ligand-based drug design. Subsequently, 12 novel compounds (26A-26L) were designed with enhanced inhibition activity and binding affinity. Molecular docking studies revealed strong and stable interactions, including hydrogen bonding and hydrophobic interactions, between the designed compounds and the target receptor. Molecular dynamics simulations over 100 nanoseconds and MM-PBSA free binding energy (ΔGbind) calculations validated the stability of the two best-designed molecules (26A and 26L). Furthermore, drug-likeness and ADMET prediction analyses affirmed the potential of these designed compounds, suggesting their promise as innovative agents for treating schistosomiasis.
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Dihidroorotato Deshidrogenasa , Diseño de Fármacos , Simulación del Acoplamiento Molecular , Simulación de Dinámica Molecular , Oxidorreductasas actuantes sobre Donantes de Grupo CH-CH , Relación Estructura-Actividad Cuantitativa , Schistosoma mansoni , Schistosoma mansoni/efectos de los fármacos , Schistosoma mansoni/enzimología , Oxidorreductasas actuantes sobre Donantes de Grupo CH-CH/antagonistas & inhibidores , Oxidorreductasas actuantes sobre Donantes de Grupo CH-CH/química , Animales , Esquistosomiasis/tratamiento farmacológico , Ligandos , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/farmacología , Humanos , Antihelmínticos/farmacología , Antihelmínticos/química , Descubrimiento de Drogas , Esquistosomiasis mansoni/tratamiento farmacológicoRESUMEN
Therapeutic antibody design has garnered widespread attention, highlighting its interdisciplinary importance. Advancements in technology emphasize the critical role of designing nanobodies and humanized antibodies in antibody engineering. However, current experimental methods are costly and time-consuming. Computational approaches, while progressing, faced limitations due to insufficient structural data and the absence of a standardized protocol. To tackle these challenges, our lab previously developed IsAb1.0, an in silico antibody design protocol. Yet, IsAb1.0 lacked accuracy, had a complex procedure, and required extensive antibody bioinformation. Moreover, it overlooked nanobody and humanized antibody design, hindering therapeutic antibody development. Building upon IsAb1.0, we enhanced our design protocol with artificial intelligence methods to create IsAb2.0. IsAb2.0 utilized AlphaFold-Multimer (2.3/3.0) for accurate modeling and complex construction without templates and employed the precise FlexddG method for in silico antibody optimization. Validated through optimization of a humanized nanobody J3 (HuJ3) targeting HIV-1 gp120, IsAb2.0 predicted five mutations that can improve HuJ3-gp120 binding affinity. These predictions were confirmed by commercial software and validated through binding and neutralization assays. IsAb2.0 streamlined antibody design, offering insights into future techniques to accelerate immunotherapy development.
Asunto(s)
Inteligencia Artificial , Ingeniería de Proteínas , Humanos , Ingeniería de Proteínas/métodos , Anticuerpos de Dominio Único/química , Anticuerpos de Dominio Único/genética , Proteína gp120 de Envoltorio del VIH/inmunología , Proteína gp120 de Envoltorio del VIH/química , Diseño de Fármacos , Simulación por ComputadorRESUMEN
Beta-amyloid (Aß), the most pivotal pathological hallmark for Alzheimer's disease (AD) diagnosis and drug evaluation, was recognized by TZ095, a high-affinity fluorescent probe developed by rational molecular design. With a TICT mechanism, TZ095 exhibited remarkable affinity with Aß aggregates (Kd = 81.54 nM for oligomers; Kd = 66.70 nM for fibril) and substantial fluorescence enhancement (F/F0 = 44), enabling real-time monitoring of Aß in live cells and nematodes. Significantly, this work used TZ095 to construct a new protocol that can quickly and conveniently monitor Aß changes at the cellular and nematode levels to evaluate the anti-AD efficacy of candidate compounds, and four reported Aß-lowering drug candidates were administrated for validation. Imaging data demonstrated that TZ095 can visually and quantitatively track the effect of Aß elimination after drug treatment. Furthermore, TZ095 excelled in ex vivo histological staining of 12-month-old APP/PS1 mouse brains, accurately visualizing Aß plaques. Integrating CUBIC technology, TZ095 facilitated whole-brain, 3D imaging of Aß distribution in APP/PS1 mice, enabling high-resolution in situ analysis of Aß plaques. Collectively, these innovative applications of TZ095 offer a promising strategy for rapid, convenient, and real-time monitoring of Aß levels in preclinical therapeutic assessments.
Asunto(s)
Enfermedad de Alzheimer , Péptidos beta-Amiloides , Diseño de Fármacos , Colorantes Fluorescentes , Enfermedad de Alzheimer/tratamiento farmacológico , Enfermedad de Alzheimer/metabolismo , Enfermedad de Alzheimer/diagnóstico por imagen , Colorantes Fluorescentes/química , Colorantes Fluorescentes/síntesis química , Colorantes Fluorescentes/farmacología , Péptidos beta-Amiloides/metabolismo , Péptidos beta-Amiloides/antagonistas & inhibidores , Animales , Humanos , Ratones , Estructura Molecular , Ratones Transgénicos , Caenorhabditis elegans/metabolismo , Caenorhabditis elegans/efectos de los fármacos , Relación Estructura-Actividad , Encéfalo/metabolismo , Encéfalo/diagnóstico por imagen , Encéfalo/patología , Relación Dosis-Respuesta a Droga , Imagen ÓpticaRESUMEN
Alzheimer's disease (AD, also known as dementia) has become a serious global health problem along with population aging, and neuroinflammation is the underlying cause of cognitive impairment in the brain. Nowadays, the development of multitarget anti-AD drugs is considered to be one effective approach. Imidazolylacetophenone oxime ethers or esters (IOEs) were multifunctional agents with neuroinflammation inhibition, metal chelation, antioxidant and neuroprotection properties against Alzheimer's disease. In this study, IOEs derivatives 1-8 were obtained by structural modifications of the oxime and imidazole groups, and the SARs showed that (Z)-oxime ether (derivative 2) had stronger anti-neuroinflammatory and neuroprotective ability than (E)-congener. Then, IOEs derivatives 9-30 were synthesized based on target-directed ligands and activity-based groups hybridization strategy. In vitro anti-AD activity screening revealed that some derivatives exhibited potentially multifunctional effects, among which derivative 28 exhibited the strongest inhibitory activity on NO production with EC50 value of 0.49 µM, and had neuroprotective effects on 6-OHDA-induced cell damage and RSL3-induced ferroptosis. The anti-neuroinflammatory mechanism showed that 28 could inhibit the release of pro-inflammatory factors PGE2 and TNF-α, down-regulate the expression of iNOS and COX-2 proteins, and promote the polarization of BV-2 cells from pro-inflammatory M1 phenotype to anti-inflammatory M2 phenotype. In addition, 28 can dose-dependently inhibit acetylcholinesterase (AChE) and Aß42 aggregation. Moreover, the selected nuclide [18F]-labeled 28 was synthesized to explore its biodistribution by micro-PET/CT, of which 28 can penetrate the blood-brain barrier (BBB). These results shed light on the potential of 28 as a new multifunctional candidate for AD treatment.
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Acetofenonas , Enfermedad de Alzheimer , Diseño de Fármacos , Imidazoles , Fármacos Neuroprotectores , Oximas , Enfermedad de Alzheimer/tratamiento farmacológico , Enfermedad de Alzheimer/metabolismo , Oximas/química , Oximas/farmacología , Oximas/síntesis química , Fármacos Neuroprotectores/farmacología , Fármacos Neuroprotectores/química , Fármacos Neuroprotectores/síntesis química , Animales , Relación Estructura-Actividad , Imidazoles/farmacología , Imidazoles/química , Imidazoles/síntesis química , Acetofenonas/química , Acetofenonas/farmacología , Acetofenonas/síntesis química , Estructura Molecular , Humanos , Encéfalo/metabolismo , Encéfalo/efectos de los fármacos , Péptidos beta-Amiloides/metabolismo , Péptidos beta-Amiloides/antagonistas & inhibidores , Acetilcolinesterasa/metabolismo , Relación Dosis-Respuesta a Droga , Ratas , Inhibidores de la Colinesterasa/farmacología , Inhibidores de la Colinesterasa/síntesis química , Inhibidores de la Colinesterasa/químicaRESUMEN
Tumor proliferation and metastasis are intricately linked to blood vessel formation, with vascular endothelial growth factor (VEGF) playing a pivotal role in orchestrating angiogenesis throughout tumor progression. Pseudolaric acid B (PAB) has emerged as a potent inhibitor of tumor cell proliferation, migration, and angiogenesis. In efforts to enhance its efficacy, 37 derivatives of PAB were synthesized and assessed for their capacity to suppress VEGF secretion in SiHa cells under hypoxic conditions. Notably, majority of these derivatives exhibited significant inhibition of VEGF protein secretion without inducing cytotoxicity. Among them, compound M2 displayed the most potent inhibitory activity, with an IC50 value of 0.68 µM, outperforming the lead compound PAB (IC50 = 5.44 µM). Compound M2 not only curbed the migration and angiogenesis of HUVECs under hypoxic conditions but also hindered the invasion of SiHa cells. Mechanistic investigations unveiled that compound M2 may impede the accumulation and nuclear translocation of hypoxia-inducible factor 1α (HIF-1α) in SiHa cells, thereby downregulating VEGF expression. This inhibitory effect on HIF-1α was corroborated by experiments utilizing the protease inhibitor MG-132 and protein synthesis inhibitor CHX, indicating that compound M2 diminishes HIF-1α levels by reducing its synthesis. Furthermore, compound M2 was observed to modulate the PI3K/AKT/mTOR and MAPK signaling pathways in tumor cells, thereby regulating HIF-1α translation and synthesis. In vivo studies demonstrated that compound M2 exhibited low toxicity and effectively curbed tumor growth. Immunohistochemistry analyses validated that compound M2 effectively suppressed the expression of HIF-1α and VEGF in tumor tissues, underscoring its potential as a promising therapeutic agent for targeting tumor angiogenesis.
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Inhibidores de la Angiogénesis , Antineoplásicos , Proliferación Celular , Diterpenos , Diseño de Fármacos , Subunidad alfa del Factor 1 Inducible por Hipoxia , Fosfatidilinositol 3-Quinasas , Proteínas Proto-Oncogénicas c-akt , Factor A de Crecimiento Endotelial Vascular , Humanos , Factor A de Crecimiento Endotelial Vascular/metabolismo , Proteínas Proto-Oncogénicas c-akt/metabolismo , Proteínas Proto-Oncogénicas c-akt/antagonistas & inhibidores , Fosfatidilinositol 3-Quinasas/metabolismo , Inhibidores de la Angiogénesis/farmacología , Inhibidores de la Angiogénesis/síntesis química , Inhibidores de la Angiogénesis/química , Proliferación Celular/efectos de los fármacos , Relación Estructura-Actividad , Antineoplásicos/farmacología , Antineoplásicos/síntesis química , Antineoplásicos/química , Subunidad alfa del Factor 1 Inducible por Hipoxia/metabolismo , Subunidad alfa del Factor 1 Inducible por Hipoxia/antagonistas & inhibidores , Diterpenos/farmacología , Diterpenos/síntesis química , Diterpenos/química , Transducción de Señal/efectos de los fármacos , Ensayos de Selección de Medicamentos Antitumorales , Estructura Molecular , Relación Dosis-Respuesta a Droga , Línea Celular Tumoral , Animales , Movimiento Celular/efectos de los fármacos , Neovascularización Patológica/tratamiento farmacológico , Neovascularización Patológica/metabolismoRESUMEN
A series of arylsulfones and heteroarylsulfones have previously been demonstrated to dysregulate the conserved bacterial ClpP protease, causing the unspecific degradation of essential cellular housekeeping proteins and ultimately resulting in cell death. A cocrystal structure of a 2-ß-sulfonylamide analog, ACP1-06, with Escherichia coli ClpP showed that its 2-pyridyl sulfonyl substituent adopts two orientations in the binding site related through a sulfone bond rotation. From this, a new bis-aryl phosphine oxide scaffold, designated as ACP6, was designed based on a "conformation merging" approach of the dual orientation of the ACP1-06 sulfone. One analog, ACP6-12, exhibited over a 10-fold increase in activity over the parent ACP1-06 compound, and a cocrystal X-ray structure with ClpP confirmed its predicted binding conformation. This allowed for a comparative analysis of how different ligand classes bind to the hydrophobic binding site. The study highlights the successful application of structure-based rational design of novel phosphine oxide-based antibiotics.
Asunto(s)
Antibacterianos , Diseño de Fármacos , Endopeptidasa Clp , Escherichia coli , Óxidos , Fosfinas , Fosfinas/química , Fosfinas/farmacología , Endopeptidasa Clp/metabolismo , Endopeptidasa Clp/antagonistas & inhibidores , Endopeptidasa Clp/química , Antibacterianos/farmacología , Antibacterianos/química , Antibacterianos/síntesis química , Óxidos/química , Escherichia coli/enzimología , Escherichia coli/efectos de los fármacos , Relación Estructura-Actividad , Proteínas de Escherichia coli/metabolismo , Proteínas de Escherichia coli/química , Proteínas de Escherichia coli/antagonistas & inhibidores , Cristalografía por Rayos X , Modelos Moleculares , Sitios de Unión , Estructura MolecularRESUMEN
The epidermal growth factor (EGF) receptor (EGFR) is activated by the binding of one of seven EGF-like ligands to its ectodomain. Ligand binding results in EGFR dimerization and stabilization of the active receptor conformation subsequently leading to activation of downstream signaling. Aberrant activation of EGFR contributes to cancer progression through EGFR overexpression/amplification, modulation of its positive and negative regulators, and/or activating mutations within EGFR. EGFR targeted therapeutic antibodies prevent dimerization and interaction with endogenous ligands by binding the ectodomain of EGFR. However, these antibodies have had limited success in the clinic, partially due to EGFR ectodomain resistance mutations, and are only applicable to a subset of patients with EGFR-driven cancers. These limitations suggest that alternative EGFR targeted biologics need to be explored for EGFR-driven cancer therapy. To this end, we analyze the EGFR interfaces of known inhibitory biologics with determined structures in the context of endogenous ligands, using the Rosetta macromolecular modeling software to highlight the most important interactions on a per-residue basis. We use this analysis to identify the structural determinants of EGFR targeted biologics. We suggest that commonly observed binding motifs serve as the basis for rational design of new EGFR targeted biologics, such as peptides, antibodies, and nanobodies.
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Receptores ErbB , Receptores ErbB/química , Receptores ErbB/antagonistas & inhibidores , Receptores ErbB/metabolismo , Receptores ErbB/genética , Humanos , Productos Biológicos/química , Productos Biológicos/farmacología , Productos Biológicos/metabolismo , Modelos Moleculares , Unión Proteica , Sitios de Unión , Diseño de Fármacos , LigandosRESUMEN
Isoxazoline insecticides have shown broad-spectrum insecticidal activity against a variety of insect pests. However, the high toxicity of isoxazoline compounds towards honeybees restricts their application in crop protection. To mitigate this issue, a series of isoxazoline derivatives containing 2-phenyloxazoline were designed and synthesized. Bioassays revealed that several compounds exhibited promising insecticidal activities against Plutella xylostella, with G28 showing particularly excellent insecticidal activity, reflected by an LC50 value of 0.675 mg/L, which is comparable to that of fluxametamide (LC50 = 0.593 mg/L). Furthermore, G28 also exhibited effective insecticidal activity against Solenopsis invicta. Importantly, bee toxicity experiments indicated that G28 had significantly lower acute oral toxicity (LD50 = 2.866 µg/adult) compared to fluxametamide (LD50 = 1.083 µg/adult) and fluralaner (LD50 = 0.022 µg/adult), positioning it as a promising candidate with reduced toxicity to bees. Theoretical simulation further elucidated the reasons for the selective differences in the ability of isoxazoline to achieve higher insecticidal activity while maintaining lower bee toxicity. This research suggests that isoxazoline compounds containing 2-phenyloxazoline group hold potential as new insecticide candidates and offers insights into the development of novel isoxazoline insecticides with both high efficacy and environmental safety.
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Diseño de Fármacos , Insecticidas , Isoxazoles , Mariposas Nocturnas , Oxazoles , Insecticidas/síntesis química , Insecticidas/química , Insecticidas/farmacología , Insecticidas/toxicidad , Animales , Oxazoles/química , Oxazoles/toxicidad , Isoxazoles/farmacología , Isoxazoles/química , Mariposas Nocturnas/efectos de los fármacos , Abejas/efectos de los fármacos , Relación Estructura-ActividadRESUMEN
The identification of new compounds with potential activity against CXC chemokine receptor type 4 (CXCR4) has been broadly studied, implying several chemical families, particularly AMD3100 derivatives. Molecular modeling has played a pivotal role in the identification of new active compounds. But, has its golden age ended? A virtual library of 450,000 tetraamines of general structure 8 was constructed by using five spacers and 300 diamines, which were obtained from the corresponding commercially available cyclic amines. Diversity selection was performed to guide the virtual screening of the former database and to select the most representative set of compounds. Molecular docking on the CXCR4 crystal structure allowed us to rank the selection and identify those candidate molecules with potential antitumor activity against diffuse large B-cell lymphoma (DLBCL). Among them, compound A{17,18} stood out for being a non-symmetrical structure, synthetically feasible, and with promising activity against DLBCL in in vitro experiments. The focused study of symmetrical-related compounds allowed us to identify potential pre-hits (IC50~20 µM), evidencing that molecular design is still relevant in the development of new CXCR4 inhibitor candidates.
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Antineoplásicos , Simulación del Acoplamiento Molecular , Receptores CXCR4 , Receptores CXCR4/antagonistas & inhibidores , Receptores CXCR4/química , Receptores CXCR4/metabolismo , Humanos , Antineoplásicos/farmacología , Antineoplásicos/química , Línea Celular Tumoral , Diseño de Fármacos , Linfoma de Células B Grandes Difuso/tratamiento farmacológico , Modelos Moleculares , Relación Estructura-ActividadRESUMEN
In recent years, extensive research has focused on cannabidiol (CBD), a well-studied non-psychoactive component of the plant-derived cannabinoids. CBD has shown significant therapeutic potential for treating various diseases and disorders, including antioxidants and anti-inflammatory effects. Due to the promising therapeutic effect of CBD in a wide variety of diseases, synthetic derivatization of this compound has attracted the attention of drug discovery in both industry and academia. In the current research, we focused on the derivatization of CBD by introducing Schiff base moieties, particularly (thio)-semicarbazide and aminoguanidine motifs, at the 3-position of the olivetolic ring. We have designed, synthesized, and characterized new derivatives based on CBD's framework, specifically aminoguanylhydrazone- and (thio)-semicarbazones-CBD-aldehyde compounds. Their antioxidant potential was assessed using FRAP and DPPH assays, alongside an evaluation of their effect on LDL oxidation induced by Cu2+ and AAPH. Our findings suggest that incorporating the thiosemicarbazide motif into the CBD framework produces a potent antioxidant, warranting further investigation.
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Antioxidantes , Cannabidiol , Diseño de Fármacos , Cannabidiol/química , Cannabidiol/farmacología , Cannabidiol/síntesis química , Antioxidantes/síntesis química , Antioxidantes/farmacología , Antioxidantes/química , Oxidación-Reducción , Semicarbacidas/química , Semicarbacidas/síntesis química , Semicarbacidas/farmacología , Lipoproteínas LDL/metabolismo , Bases de Schiff/química , Bases de Schiff/farmacología , Bases de Schiff/síntesis químicaRESUMEN
A series of new unique acetylene derivatives of 8-hydroxy- and 8-methoxyquinoline- 5-sulfonamide 3a-f and 6a-f were prepared by reactions of 8-hydroxy- and 8-methoxyquinoline- 5-sulfonyl chlorides with acetylene derivatives of amine. A series of new hybrid systems containing quinoline and 1,2,3-triazole systems 7a-h were obtained by reactions of acetylene derivatives of quinoline-5-sulfonamide 6a-d with organic azides. The structures of the obtained compounds were confirmed by 1H and 13C NMR spectroscopy and HR-MS spectrometry. The obtained quinoline derivatives 3a-f and 6a-f and 1,2,3-triazole derivatives 7a-h were tested for their anticancer and antimicrobial activity. Human amelanotic melanoma cells (C-32), human breast adenocarcinoma cells (MDA-MB-231), and human lung adenocarcinoma cells (A549) were selected as tested cancer lines, while cytotoxicity was investigated on normal human dermal fibroblasts (HFF-1). All the compounds were also tested against reference strains Staphylococcus aureus ATCC 29213 and Enterococcus faecalis ATCC 29212 and representatives of multidrug-resistant clinical isolates of methicillin-resistant S. aureus (MRSA) and vancomycin-resistant E. faecalis. Only the acetylene derivatives of 8-hydroxyquinoline-5-sulfonamide 3a-f were shown to be biologically active, and 8-hydroxy-N-methyl-N-(prop-2-yn-1-yl)quinoline-5-sulfonamide (3c) showed the highest activity against all three cancer lines and MRSA isolates. Its efficacies were comparable to those of cisplatin/doxorubicin and oxacillin/ciprofloxacin. In the non-cancer HFF-1 line, the compound showed no toxicity up to an IC50 of 100 µM. In additional tests, compound 3c decreased the expression of H3, increased the transcriptional activity of cell cycle regulators (P53 and P21 proteins), and altered the expression of BCL-2 and BAX genes in all cancer lines. The unsubstituted phenolic group at position 8 of the quinoline is the key structural fragment necessary for biological activity.
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Antibacterianos , Antineoplásicos , Pruebas de Sensibilidad Microbiana , Quinolinas , Sulfonamidas , Humanos , Antineoplásicos/farmacología , Antineoplásicos/química , Antineoplásicos/síntesis química , Antibacterianos/farmacología , Antibacterianos/química , Antibacterianos/síntesis química , Sulfonamidas/farmacología , Sulfonamidas/química , Sulfonamidas/síntesis química , Línea Celular Tumoral , Quinolinas/química , Quinolinas/farmacología , Quinolinas/síntesis química , Diseño de Fármacos , Relación Estructura-Actividad , Staphylococcus aureus/efectos de los fármacos , Enterococcus faecalis/efectos de los fármacos , Estructura MolecularRESUMEN
The enmein-type diterpenoids are a class of anticancer ent-Kaurane diterpnoids that have received much attention in recent years. Herein, a novel 1,14-epoxy enmein-type diterpenoid 4, was reported in this project for the first time. A series of novel enmein-type diterpenoid derivatives were also synthesized and tested for anticancer activities. Among all the derivatives, compound 7h exhibited the most significant inhibitory effect against A549 cells (IC50 = 2.16 µM), being 11.03-folds better than its parental compound 4. Additionally, 7h exhibited relatively weak anti-proliferative activity (IC50 > 100 µM) against human normal L-02 cells, suggesting that it had excellent anti-proliferative selectivity for cancer cells. Mechanism studies suggested that 7h induced G0/G1 arrest and apoptosis in A549 cells by inhibiting the PI3K/AKT/mTOR pathway. This process was associated with elevated intracellular ROS levels and collapsed MMP. In summary, these data identified 7h as a promising lead compound that warrants further investigation of its anticancer properties.
Asunto(s)
Antineoplásicos , Apoptosis , Proliferación Celular , Diterpenos , Fosfatidilinositol 3-Quinasas , Proteínas Proto-Oncogénicas c-akt , Transducción de Señal , Serina-Treonina Quinasas TOR , Humanos , Serina-Treonina Quinasas TOR/metabolismo , Proteínas Proto-Oncogénicas c-akt/metabolismo , Diterpenos/farmacología , Diterpenos/química , Diterpenos/síntesis química , Fosfatidilinositol 3-Quinasas/metabolismo , Transducción de Señal/efectos de los fármacos , Antineoplásicos/farmacología , Antineoplásicos/síntesis química , Antineoplásicos/química , Apoptosis/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Células A549 , Diseño de Fármacos , Línea Celular Tumoral , Relación Estructura-Actividad , Especies Reactivas de Oxígeno/metabolismoRESUMEN
As an important small organic molecule, cyclopropane is widely used in drug design. In this paper, fifty-three amide derivatives containing cyclopropane were designed and synthesized by introducing amide groups and aryl groups into cyclopropane through the active splicing method, and their antibacterial and antifungal activities were evaluated in vitro. Among them, thirty-five compounds were new compounds, and eighteen compounds were known compounds (F14, F15, F18, F20-F26, F36, and F38-F44). Bioassay results disclosed that four, three, and nine of the compounds showed moderate activity against Staphylococcus aureus, Escherichia coli, and Candida albicans, respectively. Three compounds were sensitive to Candida albicans, with excellent antifungal activity (MIC80 = 16 µg/mL). The molecular docking results show that compounds F8, F24, and F42 have good affinity with the potential antifungal drug target CYP51 protein.
Asunto(s)
Amidas , Antifúngicos , Candida albicans , Ciclopropanos , Diseño de Fármacos , Pruebas de Sensibilidad Microbiana , Simulación del Acoplamiento Molecular , Staphylococcus aureus , Ciclopropanos/farmacología , Ciclopropanos/química , Ciclopropanos/síntesis química , Amidas/química , Amidas/farmacología , Amidas/síntesis química , Candida albicans/efectos de los fármacos , Staphylococcus aureus/efectos de los fármacos , Antifúngicos/farmacología , Antifúngicos/síntesis química , Antifúngicos/química , Escherichia coli/efectos de los fármacos , Relación Estructura-Actividad , Antiinfecciosos/farmacología , Antiinfecciosos/síntesis química , Antiinfecciosos/química , Antibacterianos/farmacología , Antibacterianos/síntesis química , Antibacterianos/química , Estructura MolecularRESUMEN
By using a scaffold hopping/ring equivalent and intermediate derivatization strategies, a series of compounds of 2,5-diphenyl-1,3-oxazoline with substituent changes at the 5-phenyl position were prepared, and their acaricidal activity was studied. However, the synthesized 2,5-diphenyl-1,3-oxazolines showed lower activity against mite eggs and larvae compared to the 2,4-diphenyl-1,3-oxazolines with the same substituents. We speculate that there is a significant difference in the spatial extension direction of the substituents between the two skeletons of compounds, resulting in differences in their ability to bind to the potential target chitin synthase 1. This work is helpful in inferring the internal structure of chitin synthase binding pockets.