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1.
Biochem Pharmacol ; 174: 113823, 2020 Jan 25.
Artigo em Inglês | MEDLINE | ID: mdl-31987856

RESUMO

Supressed levels of intracellular cAMP have been associated with malignancy. Thus, elevating cAMP through activation of adenylyl cyclase (AC) or by inhibition of phosphodiesterase (PDE) may be therapeutically beneficial. Here, we demonstrate that elevated cAMP levels suppress growth in C6 cells (a model of glioma) through treatment with forskolin, an AC activator, or a range of small molecule PDE inhibitors with differing selectivity profiles. Forskolin suppressed cell growth in a PKA-dependent manner by inducing a G2/M phase cell cycle arrest. In contrast, trequinsin (a non-selective PDE2/3/7 inhibitor), not only inhibited cell growth via PKA, but also stimulated (independent of PKA) caspase-3/-7 and induced an aneuploidy phenotype. Interestingly, a cocktail of individual PDE 2,3,7 inhibitors suppressed cell growth in a manner analogous to forskolin but not trequinsin. Finally, we demonstrate that concomitant targeting of both AC and PDEs synergistically elevated intracellular cAMP levels thereby potentiating their antiproliferative actions.

2.
Chem Res Toxicol ; 33(1): 137-153, 2020 Jan 21.
Artigo em Inglês | MEDLINE | ID: mdl-31442032

RESUMO

Current in vitro models for hepatotoxicity commonly suffer from low detection rates due to incomplete coverage of bioactivity space. Additionally, in vivo exposure measures such as Cmax are used for hepatotoxicity screening and are unavailable early on. Here we propose a novel rule-based framework to extract interpretable and biologically meaningful multiconditional associations to prioritize in vitro end points for hepatotoxicity and understand the associated physicochemical conditions. The data used in this study were derived for 673 compounds from 361 ToxCast bioactivity measurements and 29 calculated physicochemical properties against two lowest effective levels (LEL) of rodent hepatotoxicity from ToxRefDB, namely 15 mg/kg/day and 500 mg/kg/day. To achieve 80% coverage of toxic compounds, 35 rules with accuracies ranging from 96% to 73% using 39 unique ToxCast assays are needed at a threshold level of 500 mg/kg/day, whereas to describe the same coverage at a threshold of 15 mg/kg/day, 20 rules with accuracies of between 98% and 81% were needed, comprising 24 unique assays. Despite the 33-fold difference in dose levels, we found relative consistency in the key mechanistic groups in rule clusters, namely (i) activities against Cytochrome P, (ii) immunological responses, and (iii) nuclear receptor activities. Less specific effects, such as oxidative stress and cell cycle arrest, were used more by rules to describe toxicity at the level of 500 mg/kg/day. Although the endocrine disruption through nuclear receptor activity formulated an essential cluster of rules, this bioactivity was not covered in four commercial assay setups for hepatotoxicity. Using an external set of 29 drugs with drug-induced liver injury (DILI) labels, we found that promiscuity over important assays discriminates between compounds with different levels of liver injury. In vitro-in vivo associations were also improved by incorporating physicochemical properties especially for the potent, 15 mg/kg/day toxicity level as well for assays describing nuclear receptor activity and phenotypic changes. The most frequently used physicochemical properties, predictive for hepatotoxicity in combination with assay activities, are linked to bioavailability, which were the number of rotatable bonds (less than 7) at a of level of 15 mg/kg/day and the number of rings (of less than 3) at level of 500 mg/kg/day. In summary, hepatotoxicity cannot very well be captured by single assay end points, but better by a combination of bioactivities in relevant assays, with the likelihood of hepatotoxicity increasing with assay promiscuity. Together, these findings can be used to prioritize assay combinations that are appropriate to assess potential hepatotoxicity.

3.
Bioorg Med Chem Lett ; 30(3): 126751, 2020 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-31862412

RESUMO

The carboxylesterase Notum is a key negative regulator of the Wnt signaling pathway by mediating the depalmitoleoylation of Wnt proteins. Our objective was to discover potent small molecule inhibitors of Notum suitable for exploring the regulation of Wnt signaling in the central nervous system. Scaffold-hopping from thienopyrimidine acids 1 and 2, supported by X-ray structure determination, identified 3-methylimidazolin-4-one amides 20-24 as potent inhibitors of Notum with activity across three orthogonal assay formats (biochemical, extra-cellular, occupancy). A preferred example 24 demonstrated good stability in mouse microsomes and plasma, and cell permeability in the MDCK-MDR1 assay albeit with modest P-gp mediated efflux. Pharmacokinetic studies with 24 were performed in vivo in mouse with single oral administration of 24 showing good plasma exposure and reasonable CNS penetration. We propose that 24 is a new chemical tool suitable for cellular studies to explore the fundamental biology of Notum.

4.
J Vis Exp ; (152)2019 Oct 20.
Artigo em Inglês | MEDLINE | ID: mdl-31680666

RESUMO

The purpose of this study is to establish a standardized and reproducible regenerative blunt spinal cord injury model in the axolotl (Ambystoma mexicanum). Most clinical spinal cord injuries occur as high energy blunt traumas, inducing contusion injuries. However, most studies in the axolotl spinal cord have been conducted with sharp traumas. Hence, this study aims to produce a more clinically relevant regenerative model. Due to their impressive ability to regenerate almost any tissue, axolotls are widely used as models in regenerative studies and have been used extensively in spinal cord injury (SCI) studies. In this protocol, the axolotls are anesthetized by submersion in a benzocaine solution. Under the microscope, an angular incision is made bilaterally at a level just caudal to the hind limbs. From this incision, it is possible to dissect and expose the spinous processes. Using forceps and scissors, a two-level laminectomy is performed, exposing the spinal cord. A custom trauma device consisting of a falling rod in a cylinder is constructed, and this device is used to induce a contusion injury to the spinal cord. The incisions are then sutured, and the animal recovers from anesthesia. The surgical approach is successful in exposing the spinal cord. The trauma mechanism can produce contusion injuries to the spinal cord, as confirmed by histology, MRI, and neurological examination. Finally, the spinal cord regenerates from the injury. The critical step of the protocol is removing the spinous processes without inflicting damage to the spinal cord. This step requires training to ensure a safe procedure. Furthermore, wound closure is highly dependent on not inflicting unnecessary damage to the skin during incision. The protocol was performed in a randomized study of 12 animals.

5.
J Chem Inf Model ; 59(10): 4150-4158, 2019 Oct 28.
Artigo em Inglês | MEDLINE | ID: mdl-31560206

RESUMO

Machine learning algorithms have attained widespread use in assessing the potential toxicities of pharmaceuticals and industrial chemicals because of their faster speed and lower cost compared to experimental bioassays. Gradient boosting is an effective algorithm that often achieves high predictivity, but historically the relative long computational time limited its applications in predicting large compound libraries or developing in silico predictive models that require frequent retraining. LightGBM, a recent improvement of the gradient boosting algorithm, inherited its high predictivity but resolved its scalability and long computational time by adopting a leaf-wise tree growth strategy and introducing novel techniques. In this study, we compared the predictive performance and the computational time of LightGBM to deep neural networks, random forests, support vector machines, and XGBoost. All algorithms were rigorously evaluated on publicly available Tox21 and mutagenicity data sets using a Bayesian optimization integrated nested 10-fold cross-validation scheme that performs hyperparameter optimization while examining model generalizability and transferability to new data. The evaluation results demonstrated that LightGBM is an effective and highly scalable algorithm offering the best predictive performance while consuming significantly shorter computational time than the other investigated algorithms across all Tox21 and mutagenicity data sets. We recommend LightGBM for applications of in silico safety assessment and also other areas of cheminformatics to fulfill the ever-growing demand for accurate and rapid prediction of various toxicity or activity related end points of large compound libraries present in the pharmaceutical and chemical industry.

6.
J Chem Inf Model ; 59(4): 1598-1604, 2019 Apr 22.
Artigo em Inglês | MEDLINE | ID: mdl-30908915

RESUMO

Multitask prediction of bioactivities is often faced with challenges relating to the sparsity of data and imbalance between different labels. We propose class conditional (Mondrian) conformal predictors using underlying Macau models as a novel approach for large scale bioactivity prediction. This approach handles both high degrees of missing data and label imbalances while still producing high quality predictive models. When applied to ten assay end points from PubChem, the models generated valid models with an efficiency of 74.0-80.1% at the 80% confidence level with similar performance both for the minority and majority class. Also when deleting progressively larger portions of the available data (0-80%) the performance of the models remained robust with only minor deterioration (reduction in efficiency between 5 and 10%). Compared to using Macau without conformal prediction the method presented here significantly improves the performance on imbalanced data sets.

7.
Drug Discov Today ; 24(5): 1193-1201, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30878561

RESUMO

Glioblastoma (GBM) remains one of the most intransigent of cancers, with a median overall survival of only 15 months after diagnosis. Drug treatments have largely proven ineffective; it is thought that this is related to the heterogeneous nature and plasticity of GBM-initiating stem cell lineages. Although many combination drug therapies are being positioned to address tumour heterogeneity, the most promising therapeutic approaches for GBM to date appear to be those targeting GBM by vaccination or antibody- and cell-based immunotherapy. We review the most recent clinical trials for GBM and discuss the role of adaptive clinical trials in developing personalised treatment strategies to address intra- and inter-tumoral heterogeneity.


Assuntos
Antineoplásicos/uso terapêutico , Neoplasias Encefálicas/tratamento farmacológico , Glioblastoma/tratamento farmacológico , Animais , Ensaios Clínicos como Assunto , Desenvolvimento de Medicamentos , Humanos
8.
Eur Radiol ; 29(4): 1848-1854, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30280250

RESUMO

OBJECTIVES: To determine meniscal extrusion and cartilage coverage on magnetic resonance (MR) images and factors associated with these parameters in knees of middle-aged and elderly persons free from radiographic tibiofemoral osteoarthritis (OA). METHODS: Seven hundred eighteen persons, free of radiographic tibiofemoral OA, aged 50-90 years from Framingham, MA, USA, were included. We measured meniscal extrusion on 1.5 T MRI of both knees to evaluate both medial and lateral meniscal body extrusion and cartilage coverage. We also determined meniscal morphology and structural integrity. The multivariable association with age, body mass index (BMI), and ipsilateral meniscal damage was also evaluated. RESULTS: The mean meniscal body extrusion medially was 2.7 mm and laterally 1.8 mm. The tibial cartilage coverage was about 30% of ipsilateral cartilage surface (both compartments). The presence of ipsilateral meniscal damage was associated with more extrusion in only the medial compartment, 1.0 mm in men and 0.6 mm in women, and less cartilage coverage proportion, -5.5% in men and -4.6% in women. CONCLUSIONS: Mean medial meniscal body extrusion in middle-aged or older persons without radiographic tibiofemoral OA approximates the commonly used cutoff (3 mm) to denote pathological extrusion. Medial meniscal damage is a factor associated with medial meniscal body extrusion and less cartilage coverage. KEY POINTS: • Medial meniscal extrusion in middle-aged/older persons without OA is around 3 mm. • Lateral meniscal extrusion in middle-aged/older persons without OA is around 2 mm. • Meniscal damage is associated with medial meniscal extrusion and less cartilage coverage.


Assuntos
Cartilagem Articular/diagnóstico por imagem , Cartilagem Articular/patologia , Articulação do Joelho/diagnóstico por imagem , Articulação do Joelho/patologia , Meniscos Tibiais/diagnóstico por imagem , Meniscos Tibiais/patologia , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Índice de Massa Corporal , Feminino , Humanos , Imagem por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Osteoartrite do Joelho
9.
Microb Ecol ; 77(2): 288-303, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30019110

RESUMO

Two annual Baltic Sea phytoplankton blooms occur in spring and summer. The bloom intensity is determined by nutrient concentrations in the water, while the period depends on weather conditions. During the course of the bloom, dead cells sink to the sediment where their degradation consumes oxygen to create hypoxic zones (< 2 mg/L dissolved oxygen). These zones prevent the establishment of benthic communities and may result in fish mortality. The aim of the study was to determine how the spring and autumn sediment chemistry and microbial community composition changed due to degradation of diatom or cyanobacterial biomass, respectively. Results from incubation of sediment cores showed some typical anaerobic microbial processes after biomass addition such as a decrease in NO2- + NO3- in the sediment surface (0-1 cm) and iron in the underlying layer (1-2 cm). In addition, an increase in NO2- + NO3- was observed in the overlying benthic water in all amended and control incubations. The combination of NO2- + NO3- diffusion plus nitrification could not account for this increase. Based on 16S rRNA gene sequences, the addition of cyanobacterial biomass during autumn caused a large increase in ferrous iron-oxidizing archaea while diatom biomass amendment during spring caused minor changes in the microbial community. Considering that OTUs sharing lineages with acidophilic microorganisms had a high relative abundance during autumn, it was suggested that specific niches developed in sediment microenvironments. These findings highlight the importance of nitrogen cycling and early microbial community changes in the sediment due to sinking phytoplankton before potential hypoxia occurs.


Assuntos
Bactérias/isolamento & purificação , Cianobactérias/crescimento & desenvolvimento , Diatomáceas/crescimento & desenvolvimento , Sedimentos Geológicos/microbiologia , Fitoplâncton/crescimento & desenvolvimento , Bactérias/classificação , Bactérias/genética , Biomassa , Cianobactérias/classificação , Cianobactérias/genética , Cianobactérias/isolamento & purificação , Diatomáceas/classificação , Diatomáceas/genética , Diatomáceas/isolamento & purificação , Eutrofização , Sedimentos Geológicos/química , Nitratos/análise , Nitratos/metabolismo , Nitritos/análise , Nitritos/metabolismo , Filogenia , Fitoplâncton/classificação , Fitoplâncton/genética , Fitoplâncton/isolamento & purificação , Estações do Ano , Água do Mar/química , Água do Mar/microbiologia
10.
Drug Resist Updat ; 40: 17-24, 2018 09.
Artigo em Inglês | MEDLINE | ID: mdl-30439622

RESUMO

Glioblastoma is the most common and malignant form of brain cancer, for which the standard treatment is maximal surgical resection, radiotherapy and chemotherapy. Despite these interventions, mean overall survival remains less than 15 months, during which extensive tumor infiltration throughout the brain occurs. The resulting metastasized cells in the brain are characterized by chemotherapy resistance and extensive intratumoral heterogeneity. An orthogonal approach attacking both intracellular resistance mechanisms as well as intercellular heterogeneity is necessary to halt tumor progression. For this reason, we established the WINDOW Consortium (Window for Improvement for Newly Diagnosed patients by Overcoming disease Worsening), in which we are establishing a strategy for rational selection and development of effective therapies against glioblastoma. Here, we overview the many challenges posed in treating glioblastoma, including selection of drug combinations that prevent therapy resistance, the need for drugs that have improved blood brain barrier penetration and strategies to counter heterogeneous cell populations within patients. Together, this forms the backbone of our strategy to attack glioblastoma.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias Encefálicas/tratamento farmacológico , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Glioblastoma/tratamento farmacológico , Bibliotecas de Moléculas Pequenas/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Barreira Hematoencefálica/metabolismo , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/patologia , Sistemas de Liberação de Medicamentos , Glioblastoma/genética , Glioblastoma/patologia , Humanos , Bibliotecas de Moléculas Pequenas/administração & dosagem , Bibliotecas de Moléculas Pequenas/efeitos adversos
11.
Chem Res Toxicol ; 31(11): 1119-1127, 2018 11 19.
Artigo em Inglês | MEDLINE | ID: mdl-30350600

RESUMO

Adverse events resulting from drug therapy can be a cause of drug withdrawal, reduced and or restricted clinical use, as well as a major economic burden for society. To increase the safety of new drugs, there is a need to better understand the mechanisms causing the adverse events. One way to derive new mechanistic hypotheses is by linking data on drug adverse events with the drugs' biological targets. In this study, we have used data mining techniques and mutual information statistical approaches to find associations between reported adverse events collected from the FDA Adverse Event Reporting System and assay outcomes from ToxCast, with the aim to generate mechanistic hypotheses related to structural cardiotoxicity (morphological damage to cardiomyocytes and/or loss of viability). Our workflow identified 22 adverse event-assay outcome associations. From these associations, 10 implicated targets could be substantiated with evidence from previous studies reported in the literature. For two of the identified targets, we also describe a more detailed mechanism, forming putative adverse outcome pathways associated with structural cardiotoxicity. Our study also highlights the difficulties deriving these type of associations from the very limited amount of data available.


Assuntos
Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos , Cardiopatias/induzido quimicamente , Modelos Teóricos , Sistemas de Notificação de Reações Adversas a Medicamentos , Animais , Mineração de Dados , Bases de Dados Factuais , Humanos , Estados Unidos , United States Food and Drug Administration
13.
Expert Opin Ther Pat ; 28(7): 573-590, 2018 07.
Artigo em Inglês | MEDLINE | ID: mdl-29950117

RESUMO

INTRODUCTION: Glioblastoma multiforme (GBM) is the most common and aggressive malignant glioma, with patients having a median survival of just over one year. Current chemotherapies, with surgery and radiotherapy, provide only minor patient benefit. There is a great need to discover and develop novel therapies for this devastating disease. Areas covered: Expert opinion: AREAS COVERED: The patent literature reveals novel therapies, providing insights into emerging GBM therapeutics. We have used the Google and USPTO patent databases to generate a detailed landscape of patents and patent applications from companies active in the areas of glioma and/or GBM. Specific patents have been grouped into six areas: novel compounds; treatments and therapeutic targets; combination therapies; immunotherapies; delivery methods; and biomarkers for diagnosis and prognosis. EXPERT OPINION: There has been a steady increase in the number of patents on GBM over the last five years. Despite many new compounds being developed and patented for a broad range of cancers, only a small percentage of these are specifically targeted to GBM. Notable trends in the patent literature include both the development of combination therapies to combat the heterogeneous nature of GBM, and the use of immunotherapies building on the promise of cancer vaccines and CAR T-cell therapy.


Assuntos
Antineoplásicos/administração & dosagem , Glioblastoma/tratamento farmacológico , Glioma/tratamento farmacológico , Animais , Biomarcadores Tumorais/metabolismo , Vacinas Anticâncer/administração & dosagem , Desenho de Drogas , Glioblastoma/patologia , Glioma/patologia , Humanos , Imunoterapia/métodos , Patentes como Assunto , Prognóstico
14.
J Chem Inf Model ; 58(5): 1132-1140, 2018 05 29.
Artigo em Inglês | MEDLINE | ID: mdl-29701973

RESUMO

Making predictions with an associated confidence is highly desirable as it facilitates decision making and resource prioritization. Conformal regression is a machine learning framework that allows the user to define the required confidence and delivers predictions that are guaranteed to be correct to the selected extent. In this study, we apply conformal regression to model molecular properties and bioactivity values and investigate different ways to scale the resultant prediction intervals to create as efficient (i.e., narrow) regressors as possible. Different algorithms to estimate the prediction uncertainty were used to normalize the prediction ranges, and the different approaches were evaluated on 29 publicly available data sets. Our results show that the most efficient conformal regressors are obtained when using the natural exponential of the ensemble standard deviation from the underlying random forest to scale the prediction intervals, but other approaches were almost as efficient. This approach afforded an average prediction range of 1.65 pIC50 units at the 80% confidence level when applied to bioactivity modeling. The choice of nonconformity function has a pronounced impact on the average prediction range with a difference of close to one log unit in bioactivity between the tightest and widest prediction range. Overall, conformal regression is a robust approach to generate bioactivity predictions with associated confidence.


Assuntos
Informática/métodos , Aprendizado de Máquina , Relação Quantitativa Estrutura-Atividade , Incerteza , Tomada de Decisões
15.
Bioinformatics ; 34(14): 2508-2509, 2018 07 15.
Artigo em Inglês | MEDLINE | ID: mdl-29522123

RESUMO

Summary: In this work, we present eMolTox, a web server for the prediction of potential toxicity associated with a given molecule. A total of 174 toxicology-related in vitro/vivo experimental datasets were used for model construction and Mondrian conformal prediction was used to estimate the confidence of the resulting predictions. Toxic substructure analysis is also implemented in eMolTox. eMolTox predicts and displays a wealth of information of potential molecular toxicities for safety analysis in drug development. Availability and implementation: The eMolTox Server is freely available for use on the web at http://xundrug.cn/moltox. Supplementary information: Supplementary data are available at Bioinformatics online.


Assuntos
Software , Toxicologia/métodos , Animais , Carcinógenos/toxicidade , Humanos , Mutagênicos/toxicidade
16.
J Cheminform ; 10(1): 7, 2018 Feb 21.
Artigo em Inglês | MEDLINE | ID: mdl-29468427

RESUMO

Iterative screening has emerged as a promising approach to increase the efficiency of screening campaigns compared to traditional high throughput approaches. By learning from a subset of the compound library, inferences on what compounds to screen next can be made by predictive models, resulting in more efficient screening. One way to evaluate screening is to consider the cost of screening compared to the gain associated with finding an active compound. In this work, we introduce a conformal predictor coupled with a gain-cost function with the aim to maximise gain in iterative screening. Using this setup we were able to show that by evaluating the predictions on the training data, very accurate predictions on what settings will produce the highest gain on the test data can be made. We evaluate the approach on 12 bioactivity datasets from PubChem training the models using 20% of the data. Depending on the settings of the gain-cost function, the settings generating the maximum gain were accurately identified in 8-10 out of the 12 datasets. Broadly, our approach can predict what strategy generates the highest gain based on the results of the cost-gain evaluation: to screen the compounds predicted to be active, to screen all the remaining data, or not to screen any additional compounds. When the algorithm indicates that the predicted active compounds should be screened, our approach also indicates what confidence level to apply in order to maximize gain. Hence, our approach facilitates decision-making and allocation of the resources where they deliver the most value by indicating in advance the likely outcome of a screening campaign.

17.
Bioinformatics ; 34(1): 72-79, 2018 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-28961699

RESUMO

Motivation: In silico approaches often fail to utilize bioactivity data available for orthologous targets due to insufficient evidence highlighting the benefit for such an approach. Deeper investigation into orthologue chemical space and its influence toward expanding compound and target coverage is necessary to improve the confidence in this practice. Results: Here we present analysis of the orthologue chemical space in ChEMBL and PubChem and its impact on target prediction. We highlight the number of conflicting bioactivities between human and orthologues is low and annotations are overall compatible. Chemical space analysis shows orthologues are chemically dissimilar to human with high intra-group similarity, suggesting they could effectively extend the chemical space modelled. Based on these observations, we show the benefit of orthologue inclusion in terms of novel target coverage. We also benchmarked predictive models using a time-series split and also using bioactivities from Chemistry Connect and HTS data available at AstraZeneca, showing that orthologue bioactivity inclusion statistically improved performance. Availability and implementation: Orthologue-based bioactivity prediction and the compound training set are available at www.github.com/lhm30/PIDGINv2. Contact: ab454@cam.ac.uk. Supplementary information: Supplementary data are available at Bioinformatics online.


Assuntos
Biologia Computacional/métodos , Simulação por Computador , Descoberta de Drogas/métodos , Proteínas/metabolismo , Homologia de Sequência de Aminoácidos , Animais , Humanos , Ligantes , Modelos Biológicos , Proteínas/efeitos dos fármacos
18.
J Med Chem ; 61(4): 1415-1424, 2018 02 22.
Artigo em Inglês | MEDLINE | ID: mdl-28800229

RESUMO

Phosphodiesterases are proving to be fruitful targets for drug discovery. At the same time fragment-based drug discovery has matured into a powerful and widely applied technique. In this communication we review the application of fragment-based drug discovery for the successful identification of novel 3',5'-cyclic nucleotide phosphodiesterase (PDE) inhibitors, concentrating on both experimental and computational strategies for fragment screening and hit-to-lead development. To this end, we also mine the open access databases ChEMBL and PDB for fragments showing PDE inhibitory activity, as well as SureChEMBL for recent PDE related patents, to provide a wider context for exploring fragment diversity. Together these approaches form an integrated experimental and computational platform to exploit fragment-based drug discovery for this important gene superfamily.


Assuntos
Descoberta de Drogas/métodos , Fragmentos de Peptídeos/uso terapêutico , Inibidores de Fosfodiesterase/química , 3',5'-AMP Cíclico Fosfodiesterases/antagonistas & inibidores , Avaliação Pré-Clínica de Medicamentos , Humanos
19.
J Chem Inf Model ; 57(3): 439-444, 2017 03 27.
Artigo em Inglês | MEDLINE | ID: mdl-28195474

RESUMO

High-throughput screening, where thousands of molecules rapidly can be assessed for activity against a protein, has been the dominating approach in drug discovery for many years. However, these methods are costly and require much time and effort. In order to suggest an improvement to this situation, in this study, we apply an iterative screening process, where an initial set of compounds are selected for screening based on molecular docking. The outcome of the initial screen is then used to classify the remaining compounds through a conformal predictor. The approach was retrospectively validated using 41 targets from the Directory of Useful Decoys, Enhanced (DUD-E), ensuring scaffold diversity among the active compounds. The results show that 57% of the remaining active compounds could be identified while only screening 9.4% of the database. The overall hit rate (7.6%) was also higher than when using docking alone (5.2%). When limiting the search to the top scored compounds from docking, 39.6% of the active compounds could be identified, compared to 13.5% when screening the same number of compounds solely based on docking. The use of conformal predictors also gives a clear indication of the number of compounds to screen in the next iteration. These results indicate that iterative screening based on molecular docking and conformal prediction can be an efficient way to find active compounds while screening only a small part of the compound collection.


Assuntos
Avaliação Pré-Clínica de Medicamentos/métodos , Simulação de Acoplamento Molecular , Ensaios de Triagem em Larga Escala , Conformação Proteica
20.
J Cheminform ; 9(1): 67, 2017 Dec 30.
Artigo em Inglês | MEDLINE | ID: mdl-29290010

RESUMO

Compounds designed to display polypharmacology may have utility in treating complex diseases, where activity at multiple targets is required to produce a clinical effect. In particular, suitable compounds may be useful in treating neurodegenerative diseases by promoting neuronal survival in a synergistic manner via their multi-target activity at the adenosine A1 and A2A receptors (A1R and A2AR) and phosphodiesterase 10A (PDE10A), which modulate intracellular cAMP levels. Hence, in this work we describe a computational method for the design of synthetically feasible ligands that bind to A1 and A2A receptors and inhibit phosphodiesterase 10A (PDE10A), involving a retrosynthetic approach employing in silico target prediction and docking, which may be generally applicable to multi-target compound design at several target classes. This approach has identified 2-aminopyridine-3-carbonitriles as the first multi-target ligands at A1R, A2AR and PDE10A, by showing agreement between the ligand and structure based predictions at these targets. The series were synthesized via an efficient one-pot scheme and validated pharmacologically as A1R/A2AR-PDE10A ligands, with IC50 values of 2.4-10.0 µM at PDE10A and Ki values of 34-294 nM at A1R and/or A2AR. Furthermore, selectivity profiling of the synthesized 2-amino-pyridin-3-carbonitriles against other subtypes of both protein families showed that the multi-target ligand 8 exhibited a minimum of twofold selectivity over all tested off-targets. In addition, both compounds 8 and 16 exhibited the desired multi-target profile, which could be considered for further functional efficacy assessment, analog modification for the improvement of selectivity towards A1R, A2AR and PDE10A collectively, and evaluation of their potential synergy in modulating cAMP levels.

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