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1.
Molecules ; 29(7)2024 Mar 31.
Artículo en Inglés | MEDLINE | ID: mdl-38611841

RESUMEN

The construction of a small molecule library that includes compounds with medium-sized rings is increasingly essential in drug discovery. These compounds are essential for identifying novel therapeutic agents capable of targeting "undruggable" targets through high-throughput and high-content screening, given their structural complexity and diversity. However, synthesizing medium-sized rings presents notable challenges, particularly with direct cyclization methods, due to issues such as transannular strain and reduced degrees of freedom. This review presents an overview of current strategies in synthesizing medium-sized rings, emphasizing innovative approaches like ring-expansion reactions. It highlights the challenges of synthesis and the potential of these compounds to diversify the chemical space for drug discovery, underscoring the importance of medium-sized rings in developing new bioactive compounds.


Asunto(s)
Descubrimiento de Drogas , Osteopatía , Biblioteca de Genes , Ciclización
2.
Expert Opin Drug Discov ; 19(5): 617-629, 2024 May.
Artículo en Inglés | MEDLINE | ID: mdl-38595031

RESUMEN

INTRODUCTION: ω-3 Polyunsaturated fatty acids (PUFAs) have a range of health benefits, including anticancer activity, and are converted to lipid mediators that could be adapted into pharmacological strategies. However, the stability of these mediators must be improved, and they may require formulation to achieve optimal tissue concentrations. AREAS COVERED: Herein, the author reviews the literature around chemical stabilization and formulation of ω-3 PUFA mediators and their application in anticancer drug discovery. EXPERT OPINION: Aryl-urea bioisosteres of ω-3 PUFA epoxides that killed cancer cells targeted the mitochondrion by a novel dual mechanism: as protonophoric uncouplers and as inhibitors of electron transport complex III that activated ER-stress and disrupted mitochondrial integrity. In contrast, aryl-ureas that contain electron-donating substituents prevented cancer cell migration. Thus, aryl-ureas represent a novel class of agents with tunable anticancer properties. Stabilized analogues of other ω-3 PUFA-derived mediators could also be adapted into anticancer strategies. Indeed, a cocktail of agents that simultaneously promote cell killing, inhibit metastasis and angiogenesis, and that attenuate the pro-inflammatory microenvironment is a novel future anticancer strategy. Such regimen may enhance anticancer drug efficacy, minimize the development of anticancer drug resistance and enhance outcomes.


Asunto(s)
Antineoplásicos , Descubrimiento de Drogas , Ácidos Grasos Omega-3 , Neoplasias , Humanos , Ácidos Grasos Omega-3/farmacología , Antineoplásicos/farmacología , Descubrimiento de Drogas/métodos , Neoplasias/tratamiento farmacológico , Neoplasias/patología , Animales , Mitocondrias/efectos de los fármacos , Mitocondrias/metabolismo
3.
Expert Opin Drug Discov ; 19(5): 565-585, 2024 May.
Artículo en Inglés | MEDLINE | ID: mdl-38509691

RESUMEN

INTRODUCTION: Human neurodevelopmental and neurodegenerative diseases (NDevDs and NDegDs, respectively) encompass a broad spectrum of disorders affecting the nervous system with an increasing incidence. In this context, the nematode C. elegans, has emerged as a benchmark model for biological research, especially in the field of neuroscience. AREAS COVERED: The authors highlight the numerous advantages of this tiny worm as a model for exploring nervous system pathologies and as a platform for drug discovery. There is a particular focus given to describing the existing models of C. elegans for the study of NDevDs and NDegDs. Specifically, the authors underscore their strong applicability in preclinical drug development. Furthermore, they place particular emphasis on detailing the common techniques employed to explore the nervous system in both healthy and diseased states. EXPERT OPINION: Drug discovery constitutes a long and expensive process. The incorporation of invertebrate models, such as C. elegans, stands as an exemplary strategy for mitigating costs and expediting timelines. The utilization of C. elegans as a platform to replicate nervous system pathologies and conduct high-throughput automated assays in the initial phases of drug discovery is pivotal for rendering therapeutic options more attainable and cost-effective.


Asunto(s)
Caenorhabditis elegans , Modelos Animales de Enfermedad , Desarrollo de Medicamentos , Descubrimiento de Drogas , Enfermedades Neurodegenerativas , Caenorhabditis elegans/efectos de los fármacos , Animales , Humanos , Descubrimiento de Drogas/métodos , Desarrollo de Medicamentos/métodos , Enfermedades Neurodegenerativas/tratamiento farmacológico , Enfermedades Neurodegenerativas/fisiopatología , Ensayos Analíticos de Alto Rendimiento/métodos , Evaluación Preclínica de Medicamentos/métodos , Trastornos del Neurodesarrollo/tratamiento farmacológico , Trastornos del Neurodesarrollo/fisiopatología , Enfermedades del Sistema Nervioso/tratamiento farmacológico , Enfermedades del Sistema Nervioso/fisiopatología
4.
Virus Res ; 344: 199359, 2024 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-38521505

RESUMEN

The heightened transmissibility and capacity of African swine fever virus (ASFV) induce fatal diseases in domestic pigs and wild boars, posing significant economic repercussions and global threats. Despite extensive research efforts, the development of potent vaccines or treatments for ASFV remains a persistent challenge. Recently, inhibiting the AsfvPolX, a key DNA repair enzyme, emerges as a feasible strategy to disrupt viral replication and control ASFV infections. In this study, a comprehensive approach involving pharmacophore-based inhibitor screening, coupled with biochemical and biophysical analyses, were implemented to identify, characterize, and validate potential inhibitors targeting AsfvPolX. The constructed pharmacophore model, Phar-PolX-S, demonstrated efficacy in identifying a potent inhibitor, D-132 (IC50 = 2.8 ± 0.2 µM), disrupting the formation of the AsfvPolX-DNA complex. Notably, D-132 exhibited strong binding to AsfvPolX (KD = 6.9 ± 2.2 µM) through a slow-on-fast-off binding mechanism. Employing molecular modeling, it was elucidated that D-132 predominantly binds in-between the palm and finger domains of AsfvPolX, with crucial residues (R42, N48, Q98, E100, F102, and F116) identified as hotspots for structure-based inhibitor optimization. Distinctively characterized by a 1,2,5,6-tetrathiocane with modifications at the 3 and 8 positions involving ethanesulfonates, D-132 holds considerable promise as a lead compound for the development of innovative agents to combat ASFV infections.


Asunto(s)
Virus de la Fiebre Porcina Africana , Antivirales , ADN Polimerasa Dirigida por ADN , Virus de la Fiebre Porcina Africana/efectos de los fármacos , Virus de la Fiebre Porcina Africana/genética , Virus de la Fiebre Porcina Africana/química , Animales , Antivirales/farmacología , Antivirales/química , Fiebre Porcina Africana/virología , Porcinos , Descubrimiento de Drogas , Replicación Viral/efectos de los fármacos , Evaluación Preclínica de Medicamentos , Unión Proteica , Simulación del Acoplamiento Molecular , ADN Viral/genética , Farmacóforo
5.
Comput Biol Med ; 173: 108339, 2024 May.
Artículo en Inglés | MEDLINE | ID: mdl-38547658

RESUMEN

The application of Artificial Intelligence (AI) to screen drug molecules with potential therapeutic effects has revolutionized the drug discovery process, with significantly lower economic cost and time consumption than the traditional drug discovery pipeline. With the great power of AI, it is possible to rapidly search the vast chemical space for potential drug-target interactions (DTIs) between candidate drug molecules and disease protein targets. However, only a small proportion of molecules have labelled DTIs, consequently limiting the performance of AI-based drug screening. To solve this problem, a machine learning-based approach with great ability to generalize DTI prediction across molecules is desirable. Many existing machine learning approaches for DTI identification failed to exploit the full information with respect to the topological structures of candidate molecules. To develop a better approach for DTI prediction, we propose GraphormerDTI, which employs the powerful Graph Transformer neural network to model molecular structures. GraphormerDTI embeds molecular graphs into vector-format representations through iterative Transformer-based message passing, which encodes molecules' structural characteristics by node centrality encoding, node spatial encoding and edge encoding. With a strong structural inductive bias, the proposed GraphormerDTI approach can effectively infer informative representations for out-of-sample molecules and as such, it is capable of predicting DTIs across molecules with an exceptional performance. GraphormerDTI integrates the Graph Transformer neural network with a 1-dimensional Convolutional Neural Network (1D-CNN) to extract the drugs' and target proteins' representations and leverages an attention mechanism to model the interactions between them. To examine GraphormerDTI's performance for DTI prediction, we conduct experiments on three benchmark datasets, where GraphormerDTI achieves a superior performance than five state-of-the-art baselines for out-of-molecule DTI prediction, including GNN-CPI, GNN-PT, DeepEmbedding-DTI, MolTrans and HyperAttentionDTI, and is on a par with the best baseline for transductive DTI prediction. The source codes and datasets are publicly accessible at https://github.com/mengmeng34/GraphormerDTI.


Asunto(s)
Inteligencia Artificial , Descubrimiento de Drogas , Evaluación Preclínica de Medicamentos , Redes Neurales de la Computación , Benchmarking
6.
Methods Mol Biol ; 2761: 159-179, 2024.
Artículo en Inglés | MEDLINE | ID: mdl-38427237

RESUMEN

Network pharmacology is an emerging pioneering approach in the drug discovery process, which is used to predict the therapeutic mechanism of compounds using various bioinformatic tools and databases. Emerging studies have indicated the use of network pharmacological approaches in various research fields, particularly in the identification of possible mechanisms of herbal compounds/ayurvedic formulations in the management of various diseases. These techniques could also play an important role in the prediction of the possible mechanisms of neuroprotective compounds. The first part of the chapter includes an introduction on neuroprotective compounds based on literature. Further, network pharmacological approaches are briefly discussed. The use of network pharmacology in the prediction of the neuroprotective mechanism of compounds is discussed in detail with suitable examples. Finally, the chapter concludes with the current challenges and future prospectives.


Asunto(s)
Medicamentos Herbarios Chinos , Farmacología en Red , Descubrimiento de Drogas , Biología Computacional , Bases de Datos Factuales , Simulación del Acoplamiento Molecular
7.
Microb Biotechnol ; 17(2): e14382, 2024 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-38345183

RESUMEN

Among the plant-associated microorganisms, the so-called endophytes continue to attract much attention because of their ability not only to protect host plants from biotic and abiotic stress factors, but also the potential to produce bioactive secondary metabolites. The latter property can elicit growth-promoting effects on plants, as well as boost the production of plant-specific secondary metabolites with valuable pharmacological properties. In addition, endophyte-derived secondary metabolites may be a rich source for the discovery of drugs to treat various diseases, including infections and cancer. However, the full potential of endophytes to produce bioactive secondary metabolites is often not revealed upon conventional cultivation in the laboratory. New advances in genomics and metabolic engineering offer exciting opportunities for the exploration and exploitation of endophytes' biosynthetic potential. This review focuses on bacterial endophytes of medicinal plants, some of their secondary metabolites and recent advances in deciphering their biosynthesis. The latter may assist in genetic engineering efforts aimed at the discovery of novel bioactive compounds with the potential to be developed into drugs.


Asunto(s)
Plantas Medicinales , Plantas Medicinales/microbiología , Endófitos/metabolismo , Descubrimiento de Drogas , Bacterias/genética
9.
Drug Discov Today ; 29(3): 103885, 2024 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-38278476

RESUMEN

Bioaffinity drug screening strategies have gained popularity in preclinical and clinical drug discovery for natural products, small molecules and antibodies owing to their superior selectivity, the large number of compounds to be screened and their ability to minimize the time and expenses of the drug discovery process. This paper provides a systematic summary of the principles of commonly used bioaffinity-based screening methods, elaborates on the success of bioaffinity in clinical drug development and summarizes the active compounds, preclinical drugs and marketed drugs obtained through affinity screening methods. Owing to the high demand for new drugs, bioaffinity-guided screening techniques will play a greater part in clinical drug development.


Asunto(s)
Productos Biológicos , Productos Biológicos/farmacología , Productos Biológicos/uso terapéutico , Descubrimiento de Drogas , Anticuerpos/uso terapéutico , Evaluación Preclínica de Medicamentos
10.
Braz J Med Biol Res ; 57: e13258, 2024.
Artículo en Inglés | MEDLINE | ID: mdl-38265347

RESUMEN

Screener, a board game supplemented with online resources, was introduced and distributed by the Brazilian Society of Pharmacology and Experimental Therapeutics to postgraduate programs as an instructional tool for the process of drug discovery and development (DDD). In this study, we provided a comprehensive analysis of five critical aspects for evaluating the quality of educational games, namely: 1) description of the intervention; 2) underlying pedagogical theory; 3) identification of local educational gaps; 4) impact on diverse stakeholders; and 5) elucidation of iterative quality enhancement processes. We also present qualitative and quantitative assessments of the effectiveness of this game in 11 postgraduate courses. We employed the MEEGA+ online survey, comprising thirty-three close-ended unipolar items with 5-point Likert-type response scales, to assess student perceptions of the quality and utility of Screener. Based on 115 responses, the results indicated a highly positive outlook among students. In addition, we performed a preliminary evaluation of learning outcomes in two courses involving 28 students. Pre- and post-quizzes were applied, each consisting of 20 True/False questions directly aligned with the game's content. The analysis revealed significant improvement in students' performance following engagement with the game, with scores rising from 8.4 to 13.3 (P<0.0001, paired t-test) and 9.7 to 12.7 (P<0.0001, paired t-test). These findings underscore the utility of Screener as an enjoyable and effective tool for facilitating a positive learning experience in the DDD process. Notably, the game can also reduce the educational disparities across different regions of our continental country.


Asunto(s)
Descubrimiento de Drogas , Aprendizaje , Humanos , Escolaridad , Brasil , Suplementos Dietéticos
11.
Mol Divers ; 28(1): 309-333, 2024 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-36790583

RESUMEN

Targeted protein degradation (TPD) technology has gradually become widespread in the past 20 years, which greatly boosts the development of disease treatment. Contrary to small inhibitors that act on protein kinases, transcription factors, ion channels, and other targets they can bind to, targeted protein degraders could target "undruggable targets" and overcome drug resistance through ubiquitin-proteasome pathway (UPP) and lysosome pathway. Nowadays, some bivalent degraders such as proteolysis-targeting chimeras (PROTACs) have aroused great interest in drug discovery, and some of them have successfully advanced into clinical trials. In this review, to better understand the mechanism of degraders, we elucidate the targeted protein degraders according to their action process, relying on the ubiquitin-proteasome system or lysosome pathway. Then, we briefly summarize the study of PROTACs employing different E3 ligases. Subsequently, the effect of protein of interest (POI) ligands, linker, and E3 ligands on PROTAC degradation activity is also discussed in detail. Other novel technologies based on UPP and lysosome pathway have been discussed in this paper such as in-cell click-formed proteolysis-targeting chimeras (CLIPTACs), molecular glues, Antibody-PROTACs (Ab-PROTACs), autophagy-targeting chimeras, and lysosome-targeting chimeras. Based on the introduction of these degradation technologies, we can clearly understand the action process and degradation mechanism of these approaches. From this perspective, it will be convenient to obtain the development status of these drugs, choose appropriate degradation methods to achieve better disease treatment and provide basis for future research and simultaneously distinguish the direction of future research efforts.


Asunto(s)
Complejo de la Endopetidasa Proteasomal , Factores de Transcripción , Suplementos Dietéticos , Descubrimiento de Drogas , Ubiquitinas , Proteolisis
12.
Bioorg Chem ; 143: 106998, 2024 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-38035513

RESUMEN

Androgen receptor (AR) plays a crucial role in various physiological processes. Dysregulation of AR signaling has been implicated in several diseases, such as prostate cancer and androgenetic alopecia. Therefore, the development of drugs that specifically target AR has gained significant attention in the field of drug discovery. This review provides an overview of the synthetic routes of clinically approved small molecule drugs targeting AR and discusses the clinical applications of these drugs in the treatment of AR-related diseases. The review also highlights the challenges and future perspectives in this field, including the need for improved drug design and the exploration of novel therapeutic targets. Through an integrated analysis of the therapeutic applications, synthetic methodologies, and mechanisms of action associated with these approved drugs, this review facilitates a holistic understanding of the versatile roles and therapeutic potential of AR-targeted interventions. Overall, this comprehensive review serves as a valuable resource for medicinal chemists interested in the development of small-molecule drugs targeting AR.


Asunto(s)
Neoplasias de la Próstata , Receptores Androgénicos , Masculino , Humanos , Neoplasias de la Próstata/tratamiento farmacológico , Descubrimiento de Drogas , Diseño de Fármacos , Transducción de Señal
13.
Stem Cell Rev Rep ; 20(2): 495-508, 2024 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-38079086

RESUMEN

Retinal diseases are leading causes of blindness globally. Developing new drugs is of great significance for preventing vision loss. Current drug discovery relies mainly on two-dimensional in vitro models and animal models, but translation to human efficacy and safety is biased. In recent years, the emergence of retinal organoid technology platforms, utilizing three-dimensional microenvironments to better mimic retinal structure and function, has provided new platforms for exploring pathogenic mechanisms and drug screening. This review summarizes the latest advances in retinal organoid technology, emphasizing its application advantages in high-throughput drug screening, efficacy and toxicity evaluation, and translational medicine research. The review also prospects the combination of emerging technologies such as organ-on-a-chip, 3D bioprinting, single cell sequencing, gene editing with retinal organoid technology, which is expected to further optimize retinal organoid models and advance the diagnosis and treatment of retinal diseases.


Asunto(s)
Organoides , Enfermedades de la Retina , Animales , Humanos , Descubrimiento de Drogas , Evaluación Preclínica de Medicamentos , Retina
14.
Planta Med ; 90(3): 172-203, 2024 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-37956978

RESUMEN

In early 2020, a global pandemic was announced due to the emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), known to cause COVID-19. Despite worldwide efforts, there are only limited options regarding antiviral drug treatments for COVID-19. Although vaccines are now available, issues such as declining efficacy against different SARS-CoV-2 variants and the aging of vaccine-induced immunity highlight the importance of finding more antiviral drugs as a second line of defense against the disease. Drug repurposing has been used to rapidly find COVID-19 therapeutic options. Due to the lack of clinical evidence for the therapeutic benefits and certain serious side effects of repurposed antivirals, the search for an antiviral drug against SARS-CoV-2 with fewer side effects continues. In recent years, numerous studies have included antiviral chemicals from a variety of plant species. A better knowledge of the possible antiviral natural products and their mechanism against SARS-CoV-2 will help to develop stronger and more targeted direct-acting antiviral agents. The aim of the present study was to compile the current data on potential plant metabolites that can be investigated in COVID-19 drug discovery and development. This review represents a collection of plant secondary metabolites and their mode of action against SARS-CoV and SARS-CoV-2.


Asunto(s)
COVID-19 , Hepatitis C Crónica , Coronavirus Relacionado al Síndrome Respiratorio Agudo Severo , Humanos , SARS-CoV-2 , Antivirales/farmacología , Antivirales/uso terapéutico , Tratamiento Farmacológico de COVID-19 , Hepatitis C Crónica/tratamiento farmacológico , Descubrimiento de Drogas
15.
SLAS Discov ; 29(1): 34-39, 2024 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-37573009

RESUMEN

Hepatic metabolic stability is a crucial determinant of oral bioavailability and plasma concentrations of a compound, and its measurement is important in early drug discovery. Preliminary metabolic stability estimations are commonly performed in liver microsomal fractions. At the National Center for Advancing Translational Sciences, a single-point assay in rat liver microsomes (RLM) is employed for initial stability assessment (Tier I) and a multi-point detailed stability assay is employed as a Tier II assay for promising compounds. Although the in vitro and in vivo metabolic stability of compounds typically exhibit good correlation, conflicting results may arise in certain cases. While investigating one such instance, we serendipitously found vendor-related RLM differences in metabolic stability and metabolite formation, which had implications for in vitro and in vivo correlations. In this study, we highlight the importance of considering vendor differences in hepatic metabolic stability data and discuss strategies to avoid these pitfalls.


Asunto(s)
Descubrimiento de Drogas , Hígado , Ratas , Animales , Hígado/metabolismo , Descubrimiento de Drogas/métodos , Microsomas Hepáticos/metabolismo , Disponibilidad Biológica , Evaluación Preclínica de Medicamentos/métodos
16.
J Pharm Sci ; 113(1): 118-130, 2024 01.
Artículo en Inglés | MEDLINE | ID: mdl-37634869

RESUMEN

In-vitro models are available in the literature for predicting the volume of distribution at steady-state (Vdss) of drugs. The mechanistic model refers to the tissue composition-based model (TCM), which includes important factors that govern Vdss such as drug physiochemistry and physiological data. The recognized TCM published by Rodgers and Rowland (TCM-RR) and a subsequent adjustment made by Simulations Plus Inc. (TCM-SP) have been shown to be generally less accurate with neutral compared to ionized drugs. Therefore, improving these models for neutral drugs becomes necessary. The objective of this study was to propose a new TCM for improving the prediction of Vdss for neutral drugs. The new TCM included two modifications of the published models (i) accentuate the effect of the blood-to-plasma ratio (BPR) that should cover permeated molecules across the biomembranes, which is lacking in these models for neutral compounds, and (ii) use a different approach to estimate the binding in tissues. The new TCM was validated with a large dataset of 202 commercial and proprietary compounds including preclinical and clinical data. All scenario datasets were predicted more accurately with the TCM-New, whereas all statistical parameters indicate that the TCM-New showed significant improvements in terms of accuracy over the TCM-RR and TCM-SP. Predictions of Vdss were frequently more accurate for the TCM-new with 83% within twofold error versus only 50% for the TCM-RR. And more than 95% of the predictions were within threefold error and patient interindividual differences can be predicted with the TCM-New, greatly exceeding the accuracy of the published models. Overall, the new TCM incorporating BPR significantly improved the Vdss predictions in animals and humans for neutral drugs, and, hence, has the potential to better support the drug discovery and facilitate the first-in-human predictions.


Asunto(s)
Descubrimiento de Drogas , Modelos Biológicos , Animales , Humanos , Especificidad de la Especie , Evaluación Preclínica de Medicamentos , Unión Proteica , Preparaciones Farmacéuticas , Farmacocinética
17.
Biomaterials ; 304: 122408, 2024 01.
Artículo en Inglés | MEDLINE | ID: mdl-38041911

RESUMEN

The limitations of traditional two-dimensional (2D) cultures and animal testing, when it comes to precisely foreseeing the toxicity and clinical effectiveness of potential drug candidates, have resulted in a notable increase in the rate of failure during the process of drug discovery and development. Three-dimensional (3D) in-vitro models have arisen as substitute platforms with the capacity to accurately depict in-vivo conditions and increasing the predictivity of clinical effects and toxicity of drug candidates. It has been found that 3D models can accurately represent complex tissue structure of human body and can be used for a wide range of disease modeling purposes. Recently, substantial progress in biomedicine, materials and engineering have been made to fabricate various 3D in-vitro models, which have been exhibited better disease progression predictivity and drug effects than convention models, suggesting a promising direction in pharmaceutics. This comprehensive review highlights the recent developments in 3D in-vitro tissue models for preclinical applications including drug screening and disease modeling targeting multiple organs and tissues, like liver, bone, gastrointestinal tract, kidney, heart, brain, and cartilage. We discuss current strategies for fabricating 3D models for specific organs with their strengths and pitfalls. We expand future considerations for establishing a physiologically-relevant microenvironment for growing 3D models and also provide readers with a perspective on intellectual property, industry, and regulatory landscape.


Asunto(s)
Bioimpresión , Ingeniería de Tejidos , Animales , Humanos , Ingeniería de Tejidos/métodos , Bioimpresión/métodos , Descubrimiento de Drogas , Evaluación Preclínica de Medicamentos , Impresión Tridimensional
18.
Expert Opin Drug Discov ; 19(3): 339-351, 2024 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-38117223

RESUMEN

INTRODUCTION: Vascular diseases impart a tremendous burden on healthcare systems in the United States and across the world. Efforts to improve therapeutic interventions are hindered by limitations of current experimental models. The integration of patient-derived cells with organ-on-chip (OoC) technology is a promising avenue for preclinical drug screening that improves upon traditional cell culture and animal models. AREAS COVERED: The authors review induced pluripotent stem cells (iPSC) and blood outgrowth endothelial cells (BOEC) as two sources for patient-derived endothelial cells (EC). They summarize several studies that leverage patient-derived EC and OoC for precision disease modeling of the vasculature, with a focus on applications for drug discovery. They also highlight the utility of patient-derived EC in other translational endeavors, including ex vivo organogenesis and multi-organ-chip integration. EXPERT OPINION: Precision disease modeling continues to mature in the academic space, but end-use by pharmaceutical companies is currently limited. To fully realize their transformative potential, OoC systems must balance their complexity with their ability to integrate with the highly standardized and high-throughput experimentation required for drug discovery and development.


Asunto(s)
Células Endoteliales , Células Madre Pluripotentes Inducidas , Animales , Humanos , Descubrimiento de Drogas , Evaluación Preclínica de Medicamentos , Dispositivos Laboratorio en un Chip
19.
Nat Prod Res ; 38(1): 37-42, 2024.
Artículo en Inglés | MEDLINE | ID: mdl-35866987

RESUMEN

Secondary metabolites extracted from plants have historically been critical for drug discovery, but their isolation involves expensive and complicated procedures in terms of time and labor resources. Thus, the biogenetic pathway offers the possibility of identifying specific compounds that have not yet been isolated and predicting their isolation from specific natural sources. In plants, biphenanthrenes represent a relatively small group of aromatic secondary metabolites that are considered as important taxonomic markers with promising biological activities. To date, 38 mixed phenanthrenoid dimers have been identified, the biosynthesis of which involves the radical coupling of the two subunits, namely, a phenanthrene and a dihydrophenanthrene. For each of the compounds, it is possible to identify the single phenanthrenic and dihydrophenanthrenic units constituting the considered dimer. Based on the biogenetic pathway, it is possible to identify 19 phenanthrenes and 17 dihydrophenanthrenes, and to distinguish those already known from those not yet isolated. By comparing the results of the possible biosynthetic pathway for each compound with the data in the literature, it is possible to identify three known phenanthrenes and seven known dihydrophenanthrenes, as well as eleven new phenanthrenes and five new dihydrophenanthrenes, and to identify from which plant it is possible to isolate them. This could direct the work of researchers seeking to identify known or new molecules useful for their possible biological properties, and ultimately, to confirm the veracity of the proposed and generally accepted biosynthetic pathway.


Asunto(s)
Vías Biosintéticas , Fenantrenos , Extractos Vegetales , Descubrimiento de Drogas
20.
Int J Mol Sci ; 24(23)2023 Nov 25.
Artículo en Inglés | MEDLINE | ID: mdl-38069085

RESUMEN

Condition-based molecular generation can generate a large number of molecules with particular properties, expanding the virtual drug screening library, and accelerating the process of drug discovery. In this study, we combined a molecular graph structure and sequential representations using a generative pretrained transformer (GPT) architecture for generating molecules conditionally. The incorporation of graph structure information facilitated a better comprehension of molecular topological features, and the augmentation of a sequential contextual understanding of GPT architecture facilitated molecular generation. The experiments indicate that our model efficiently produces molecules with the desired properties, with valid and unique metrics that are close to 100%. Faced with the typical task of generating molecules based on a scaffold in drug discovery, our model is able to preserve scaffold information and generate molecules with low similarity and specified properties.


Asunto(s)
Benchmarking , Descubrimiento de Drogas , Evaluación Preclínica de Medicamentos , Suministros de Energía Eléctrica
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