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1.
Expert Opin Ther Pat ; 30(1): 15-25, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31847622

RESUMO

Introduction: Worldwide, the annual expenditure on anticancer drugs is grossly calculated to be in the order of US$100 billion, and is expected to escalate up to $150 billion by 2020. It is evident that the vast majority of the most recently devised anticancer drugs are unaffordable in economically developing nations, frequently resulting in subpar therapies. In this complex medical and economic scenario, the repurposing of older drugs for anticancer therapies becomes a necessity. The repurposing of antiacid drugs such as the proton pump inhibitors as antitumoral agents and chemosensitizers is probably one of the most recent and promising phenomenon in oncology.Areas covered: Important research articles and patents focusing on proton pump inhibitors as a potential class of therapeutics, published between the period of 2006-2019, have been covered. This review mainly focuses on the therapeutic applications, as direct anticancer agents as well as modifiers of the tumor microenvironment and modulator of chemoresistance.Expert opinion: PPIs have significant anticancer applications and are proving to be safe, effective and inexpensive. Here the authors review the current knowledge regarding the influence of PPIs on the efficacy and safety of cancer chemotherapeutics through the regulation of targets other than the H+/K+-ATPase.


Assuntos
Antineoplásicos/farmacologia , Reposicionamento de Medicamentos , Inibidores da Bomba de Prótons/farmacologia , Animais , Antineoplásicos/administração & dosagem , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Humanos , Neoplasias/tratamento farmacológico , Patentes como Assunto , Inibidores da Bomba de Prótons/administração & dosagem , Microambiente Tumoral/efeitos dos fármacos
2.
BMC Bioinformatics ; 20(Suppl 26): 628, 2019 Dec 16.
Artigo em Inglês | MEDLINE | ID: mdl-31839008

RESUMO

BACKGROUND: Development of new drugs is a time-consuming and costly process, and the cost is still increasing in recent years. However, the number of drugs approved by FDA every year per dollar spent on development is declining. Drug repositioning, which aims to find new use of existing drugs, attracts attention of pharmaceutical researchers due to its high efficiency. A variety of computational methods for drug repositioning have been proposed based on machine learning approaches, network-based approaches, matrix decomposition approaches, etc. RESULTS: We propose a novel computational method for drug repositioning. We construct and decompose three-dimensional tensors, which consist of the associations among drugs, targets and diseases, to derive latent factors reflecting the functional patterns of the three kinds of entities. The proposed method outperforms several baseline methods in recovering missing associations. Most of the top predictions are validated by literature search and computational docking. Latent factors are used to cluster the drugs, targets and diseases into functional groups. Topological Data Analysis (TDA) is applied to investigate the properties of the clusters. We find that the latent factors are able to capture the functional patterns and underlying molecular mechanisms of drugs, targets and diseases. In addition, we focus on repurposing drugs for cancer and discover not only new therapeutic use but also adverse effects of the drugs. In the in-depth study of associations among the clusters of drugs, targets and cancer subtypes, we find there exist strong associations between particular clusters. CONCLUSIONS: The proposed method is able to recover missing associations, discover new predictions and uncover functional clusters of drugs, targets and diseases. The clustering of drugs, targets and diseases, as well as the associations among the clusters, provides a new guiding framework for drug repositioning.


Assuntos
Biologia Computacional , Reposicionamento de Medicamentos , Análise por Conglomerados , Biologia Computacional/métodos , Reposicionamento de Medicamentos/métodos , Humanos , Aprendizado de Máquina
5.
BMC Bioinformatics ; 20(1): 577, 2019 Nov 14.
Artigo em Inglês | MEDLINE | ID: mdl-31726977

RESUMO

BACKGROUND: De novo drug discovery is a time-consuming and expensive process. Nowadays, drug repositioning is utilized as a common strategy to discover a new drug indication for existing drugs. This strategy is mostly used in cases with a limited number of candidate pairs of drugs and diseases. In other words, they are not scalable to a large number of drugs and diseases. Most of the in-silico methods mainly focus on linear approaches while non-linear models are still scarce for new indication predictions. Therefore, applying non-linear computational approaches can offer an opportunity to predict possible drug repositioning candidates. RESULTS: In this study, we present a non-linear method for drug repositioning. We extract four drug features and two disease features to find the semantic relations between drugs and diseases. We utilize deep learning to extract an efficient representation for each feature. These representations reduce the dimension and heterogeneity of biological data. Then, we assess the performance of different combinations of drug features to introduce a pipeline for drug repositioning. In the available database, there are different numbers of known drug-disease associations corresponding to each combination of drug features. Our assessment shows that as the numbers of drug features increase, the numbers of available drugs decrease. Thus, the proposed method with large numbers of drug features is as accurate as small numbers. CONCLUSION: Our pipeline predicts new indications for existing drugs systematically, in a more cost-effective way and shorter timeline. We assess the pipeline to discover the potential drug-disease associations based on cross-validation experiments and some clinical trial studies.


Assuntos
Aprendizado Profundo , Reposicionamento de Medicamentos , Preparações Farmacêuticas , Área Sob a Curva , Doença , Humanos , Análise de Componente Principal
6.
Eur J Pharm Sci ; 140: 105092, 2019 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-31634556

RESUMO

5-nitrofurans (NFs) have been in clinical use for over 60 years. These affordable drugs are used for the treatment of a broad spectrum of diseases ranging from urinary tract infections to cancer. The anti-pathogenic effect of clinical NFs occurs following a step-wise process involving activation by azoreduction, followed by nitroreduction catalysed by azoreductases and nitroreductases (NTRs), respectively. Azoreduction yields stable metabolites that have the ability to covalently bind to cellular proteins. Nitroreduction, on the other hand, occurs by type I or II reduction of the nitro group in the presence of parasitic NADPH-cytochrome P450 reductases. Type I NTRs catalyse, under anaerobic conditions, the reduction of NFs to produce anti-pathogenic hydroxylamine. Under aerobic conditions, nitroreduction catalysed by type II NTRs produces reactive oxygen and nitrogen species (ROS/RNS), causing oxidative stress to pathogens and ultimate death. This multi-activity nature of NFs thus allows the repurposing of these drugs from agricultural chemicals and basic antibiotics to efficient therapies against human life-threatening diseases. Cases of NF resistance in pathogens are also limited likely due to this multi-activity, as well as effectivity under both aerobic and anaerobic conditions. However, multi-activity of these drugs can also infer toxicity. Molecular derivatisation is an effective strategy to improve efficacy, lower toxicity, diversify activity and address pathogen resistance associated with the use of these drugs.


Assuntos
Antibacterianos/farmacologia , Reposicionamento de Medicamentos/métodos , Nitrofuranos/farmacologia , Antibacterianos/toxicidade , Catálise , Avaliação Pré-Clínica de Medicamentos/métodos , Resistência Microbiana a Medicamentos/efeitos dos fármacos , Humanos , Estrutura Molecular , NADH NADPH Oxirredutases/metabolismo , NADPH-Ferri-Hemoproteína Redutase/metabolismo , Nitrofuranos/toxicidade , Nitrogênio/química , Nitrorredutases/metabolismo , Oxirredução , Estresse Oxidativo/efeitos dos fármacos , Espécies Reativas de Oxigênio/metabolismo , Relação Estrutura-Atividade
7.
Fitoterapia ; 139: 104371, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31629051

RESUMO

Extrusion of drugs or drug-like compounds through bacterial efflux pumps is a serious health issue that leads to loss in drug efficacy. Combinatorial therapies of low-efficacy drugs with efflux pump inhibitors may help to restore the activities of such drugs. In this quest, natural products are attractive molecules, since in addition to their wide range of bioactivities they may inhibit efflux pumps. The current work repurposed the bioactive alkaloid roemerine as a potential efflux pump inhibitor. In Bacillus subtilis, both Bmr and BmrA, belonging to the major facilitator and the ATP-binding cassette superfamilies, respectively, were found to be inhibited by roemerine. Scanning electron microscopy and RNA-Seq analyses showed that it potentiated the effect of berberine. Growth rates and checkerboard assays confirmed the synergy of roemerine and berberine and that roemerine prevented berberine efflux by inhibiting Bmr. Transport assays with inverted membrane vesicles prepared from Escherichia coli overexpressing BmrA showed that increasing roemerine concentration decreased the transport of doxorubicin, the BmrA substrate, confirming that roemerine may also be considered as an inhibitor of BmrA. Thus, these findings suggest that conjugation of roemerine to substrates of efflux pumps, Bmr and BmrA, may help to potentiate the activity of their drug substrates.


Assuntos
Antibacterianos/farmacologia , Aporfinas/farmacologia , Proteínas de Bactérias/antagonistas & inibidores , Alcaloides/farmacologia , Bacillus subtilis/efeitos dos fármacos , Berberina/farmacologia , Transporte Biológico , Reposicionamento de Medicamentos , Sinergismo Farmacológico , Escherichia coli/efeitos dos fármacos , Proteínas de Membrana Transportadoras , Testes de Sensibilidade Microbiana , Estrutura Molecular , Papaver/química , Componentes Aéreos da Planta/química , Turquia
8.
Expert Opin Ther Pat ; 29(10): 781-792, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31596641

RESUMO

Introduction: Glaucoma affects more than 70 million people worldwide. One of the major therapeutic options for its management is based on the inhibition of the metalloenzyme carbonic anhydrases (CAs, EC 4.2.1.1). CA inhibitors (CAIs) diminish ocular hypertension in glaucomatous patients by reducing the rate of bicarbonate formation and thus, the secretion of the aqueous humor. Areas covered: This review is intended to cover the major contributions in terms of patent literature reports for the treatment of ophthalmic diseases by means of CAIs in a time frame spanning from 2013 to date. Expert opinion: The patent literature is dominated by innovative pharmaceutical formulations including a CAI alone or in combination with other therapeutic agents. Very few novelties within drug discovery are currently present and they mainly account for new CAI moieties and classical CAIs merged into scaffolds bearing additional chemical functionalities beneficial for the pharmacological treatment of the disease. It is reasonable to expect that in the near future the so-called 'old drugs' will achieve pharmacological performances in the management of ocular hypertension beyond any expectations and thus open a new era of drug repurposing merely based on material science advancements.


Assuntos
Inibidores da Anidrase Carbônica/administração & dosagem , Glaucoma/tratamento farmacológico , Hipertensão Ocular/tratamento farmacológico , Animais , Inibidores da Anidrase Carbônica/farmacologia , Anidrases Carbônicas/efeitos dos fármacos , Anidrases Carbônicas/metabolismo , Desenho de Drogas , Reposicionamento de Medicamentos , Glaucoma/enzimologia , Humanos , Hipertensão Ocular/enzimologia , Patentes como Assunto
10.
Neoplasma ; 66(6): 963-970, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31607128

RESUMO

Triple negative breast cancer (TNBC) is a particularly aggressive subtype of breast cancer (BC) for which limited therapeutic options are available. Recently, ß-blockers (BBs) have been suggested to have favorable effects in the treatment of BC. The aim of this systematic review was to collect evidence from preclinical and clinical studies concerning the scientific evidence for the repurposing of BBs in TNBC treatment. PubMed database was searched to retrieve studies of interest published up to 30/01/2018. All preclinical studies using TNBC in vitro and in vivo models and assessing the effect of any molecule with sympatholytic or sympathomimetic activity on adrenergic receptors were included. Clinical studies concerning BBs were considered eligible. The Newcastle-Ottawa scale was used for the quality assessment of clinical studies. A total of 614 study references were retrieved. Forty-six preclinical studies were included. In in vitro studies, propranolol, a non-selective BB, significantly decreased proliferation, migration and invasion of TNBC cells. Consistently, in in vivo studies, propranolol inhibited metastasis, angiogenesis and tumor growth. Clinical studies, reporting evidence from a total of four distinct retrospective observational cohort studies, showed a beneficial effect of BBs in TNBC treatment. The overall quality of the clinical evidence collected was low. Preclinical evidence collected in this systematic review are in line with the results reported in the clinical studies retrieved, pointing towards a beneficial effect of BB in the treatment of TNBC. However, given the overall low quality of available evidence, no definite conclusion may be drawn.


Assuntos
Antagonistas Adrenérgicos beta/uso terapêutico , Reposicionamento de Medicamentos , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Linhagem Celular Tumoral , Proliferação de Células , Humanos , Neovascularização Patológica , Estudos Observacionais como Assunto , Estudos Retrospectivos
11.
Life Sci ; 236: 116889, 2019 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-31610199

RESUMO

Stroke is the major cause of adult disability and the second or third leading cause of death in developed countries. The treatment options for stroke (thrombolysis or thrombectomy) are restricted to a small subset of patients with acute ischemic stroke because of the limited time for an efficacious response and the strict criteria applied to minimize the risk of cerebral hemorrhage. Attempts to develop new treatments, such as neuroprotectants, for acute ischemic stroke have been costly and time-consuming and to date have yielded disappointing results. The repurposing approved drugs known to be relatively safe, such as statins and minocycline, may provide a less costly and more rapid alternative to new drug discovery in this clinical condition. Because adequate perfusion is thought to be vital for a neuroprotectant to be effective, endovascular thrombectomy (EVT) with advanced imaging modalities offers the possibility of documenting reperfusion in occluded large cerebral vessels. An examination of established medications that possess neuroprotective characters using in a large-vessel occlusive disorder with EVT may speed the identification of new and more broadly efficacious medications for the treatment of ischemic stroke. These approaches are highlighted in this review along with a critical assessment of drug repurposing combined with reperfusion therapy as a supplementary means for halting or mitigating stroke-induced brain damage.


Assuntos
Isquemia Encefálica/terapia , Hemorragia Cerebral/terapia , Reposicionamento de Medicamentos , Procedimentos Endovasculares/métodos , Acidente Vascular Cerebral/terapia , Trombectomia/métodos , Terapia Trombolítica/métodos , Terapia Combinada , Humanos , Reperfusão , Resultado do Tratamento
12.
Nature ; 574(7776): 127-131, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31570881

RESUMO

The large-scale genetic profiling of tumours can identify potentially actionable molecular variants for which approved anticancer drugs are available1-3. However, when patients with such variants are treated with drugs outside of their approved label, successes and failures of targeted therapy are not systematically collected or shared. We therefore initiated the Drug Rediscovery protocol, an adaptive, precision-oncology trial that aims to identify signals of activity in cohorts of patients, with defined tumour types and molecular variants, who are being treated with anticancer drugs outside of their approved label. To be eligible for the trial, patients have to have exhausted or declined standard therapies, and have malignancies with potentially actionable variants for which no approved anticancer drugs are available. Here we show an overall rate of clinical benefit-defined as complete or partial response, or as stable disease beyond 16 weeks-of 34% in 215 treated patients, comprising 136 patients who received targeted therapies and 79 patients who received immunotherapy. The overall median duration of clinical benefit was 9 months (95% confidence interval of 8-11 months), including 26 patients who were experiencing ongoing clinical benefit at data cut-off. The potential of the Drug Rediscovery protocol is illustrated by the identification of a successful cohort of patients with microsatellite instable tumours who received nivolumab (clinical benefit rate of 63%), and a cohort of patients with colorectal cancer with relatively low mutational load who experienced only limited clinical benefit from immunotherapy. The Drug Rediscovery protocol facilitates the defined use of approved drugs beyond their labels in rare subgroups of cancer, identifies early signals of activity in these subgroups, accelerates the clinical translation of new insights into the use of anticancer drugs outside of their approved label, and creates a publicly available repository of knowledge for future decision-making.


Assuntos
Antineoplásicos/uso terapêutico , Descoberta de Drogas/métodos , Reposicionamento de Medicamentos/tendências , Neoplasias/tratamento farmacológico , Adulto , Idoso , Idoso de 80 Anos ou mais , Estudos de Coortes , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/genética , Feminino , Humanos , Imunoterapia , Masculino , Pessoa de Meia-Idade , Terapia de Alvo Molecular , Neoplasias/genética , Nivolumabe/uso terapêutico , Medicina de Precisão , Intervalo Livre de Progressão , Projetos de Pesquisa , Adulto Jovem
13.
Cancer Treat Rev ; 80: 101896, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31541850

RESUMO

Glioblastomas are intrinsic brain tumors thought to originate from neuroglial stem or progenitor cells. More than 90% of glioblastomas are isocitrate dehydrogenase (IDH)-wildtype tumors. Incidence increases with age, males are more often affected. Beyond rare instances of genetic predisposition and irradiation exposure, there are no known glioblastoma risk factors. Surgery as safely feasible followed by involved-field radiotherapy plus concomitant and maintenance temozolomide chemotherapy define the standard of care since 2005. Except for prolonged progression-free, but not overall survival afforded by the vascular endothelial growth factor antibody, bevacizumab, no pharmacological intervention has been demonstrated to alter the course of disease. Specifically, targeting cellular pathways frequently altered in glioblastoma, such as the phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT)/mammalian target of rapamycin (mTOR), the p53 and the retinoblastoma (RB) pathways, or epidermal growth factor receptor (EGFR) gene amplification or mutation, have failed to improve outcome, likely because of redundant compensatory mechanisms, insufficient target coverage related in part to the blood brain barrier, or poor tolerability and safety. Yet, uncommon glioblastoma subsets may exhibit specific vulnerabilities amenable to targeted interventions, including, but not limited to: high tumor mutational burden, BRAF mutation, neurotrophic tryrosine receptor kinase (NTRK) or fibroblast growth factor receptor (FGFR) gene fusions, and MET gene amplification or fusions. There is increasing interest in targeting not only the tumor cells, but also the microenvironment, including blood vessels, the monocyte/macrophage/microglia compartment, or T cells. Improved clinical trial designs using pharmacodynamic endpoints in enriched patient populations will be required to develop better treatments for glioblastoma.


Assuntos
Antineoplásicos/farmacologia , Neoplasias Encefálicas/tratamento farmacológico , Glioblastoma/tratamento farmacológico , Antineoplásicos/uso terapêutico , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/metabolismo , Reposicionamento de Medicamentos , Glioblastoma/genética , Glioblastoma/metabolismo , Humanos , Terapia de Alvo Molecular , Ensaios Clínicos Controlados Aleatórios como Assunto
15.
Brain Nerve ; 71(9): 936-942, 2019 Sep.
Artigo em Japonês | MEDLINE | ID: mdl-31506395

RESUMO

The aim of drug repositioning is to identify and develop new uses for existing drugs. Many drugs for neurological disorders have been established by drug repositioning. Conventional drug repositioning approaches are based on chance findings or close clinical observations. Nowadays, computational drug repositioning can complement these approaches. Drug repositioning has many advantages. For example, unexpected adverse events occur less frequently in clinical trials using repositioned drugs than in trials with new drugs because safety information for repositioned drugs has often already accumulated before the start of a clinical trial. Another advantage is that drug repositioning can shorten the time needed for drug development and thereby reduce costs related to drug innovation. If results of pharmacological and toxic tests are available, pre-clinical studies may also be omitted. Drug repositioning is especially promising in the development of treatments for neurodegenerative disorders because the development of new drugs for chronic disorders often takes more than 20 years and has a high financial burden. Strategic patenting is important to cooperate with pharmaceutical companies and to accomplish drug repositioning.


Assuntos
Reposicionamento de Medicamentos , Doenças Neurodegenerativas/tratamento farmacológico , Humanos
16.
Brain Nerve ; 71(9): 953-959, 2019 Sep.
Artigo em Japonês | MEDLINE | ID: mdl-31506397

RESUMO

Among the therapeutic agents for Parkinson's disease (PD), there are important drugs that precede drug repositioning. Amantadine, developed as a treatment for influenza A, has been long used as a treatment for PD. Zonisamide is an antiepileptic drug developed in Japan, where its therapeutic effects on PD were also discovered and developed. In recent years, dabrafenib, a therapeutic agent for malignant melanoma, has bean identified as a potential therapeutic agent for PD. Amantadine and zonisamide are drugs that have been serendipitously developed in clinical settings for patients with PD. Meanwhile, the potential for repurposing dabrafenib was discovered by utilizing the results of genome-wide association studies, drug databases, and protein-protein interaction databases.


Assuntos
Amantadina/uso terapêutico , Antiparkinsonianos/uso terapêutico , Imidazóis/uso terapêutico , Oximas/uso terapêutico , Doença de Parkinson/tratamento farmacológico , Zonisamida/uso terapêutico , Reposicionamento de Medicamentos , Estudo de Associação Genômica Ampla , Humanos
17.
Brain Nerve ; 71(9): 961-970, 2019 Sep.
Artigo em Japonês | MEDLINE | ID: mdl-31506398

RESUMO

To date, all clinical trials of disease-modifying drugs for Alzheimer's disease (AD) have been unsuccessful, making investments into AD drug development very risky despite the high unmet need. Drug repositioning or repurposing approaches are relatively less expensive and more promising compared to novel drug development in AD. About 40% of clinical trials for AD currently in progress across the world use the drug repositioning method. They are expected to be a trigger for AD drug discovery that breaks the current deadlock situation. By using drugs approved for other indications, these clinical trials target dysregulated pathways of AD with different or a combination of modes of action, including anti-amyloid, anti-tau, anti-inflammatory, metabolic, neuroprotective, and neurotransmission-based approaches. In these clinical trials, cardiovascular drugs such as insulin, cilostazol, probucol, telmisartan, and dabigatran are tested for their effect on different mechanisms of AD pathology. This is in line with the recent emphasis that AD should be studied as a complex multifactorial disorder, not dominated by one dominant biological factor such as beta-amyloid, and without disregarding any relevant pathologic factor, such as vascular dysregulation. It is strongly expected that drug repositioning approaches will create a paradigm shift in treatment approaches for AD patients.


Assuntos
Doença de Alzheimer/tratamento farmacológico , Reposicionamento de Medicamentos , Cilostazol , Dabigatrana , Humanos , Insulina , Probucol , Telmisartan
18.
Brain Nerve ; 71(9): 981-989, 2019 Sep.
Artigo em Japonês | MEDLINE | ID: mdl-31506400

RESUMO

The methodologies of computational drug discovery and drug repositioning (DR) based on biomolecular profile information are reviewed systematically. For big data drug discovery and DR, 1) methods of comparing gene expression profiles of the diseased state and drug-administered state to predict the effect and toxicity of the drug, 2) DR methods based on the disease network, and 3) prediction of drug effect based on the biological network analysis are described. For methods of AI-based drug discovery, virtual screening using AI and AI-based drug target exploration are reviewed.


Assuntos
Inteligência Artificial , Descoberta de Drogas , Reposicionamento de Medicamentos
19.
Cell Biochem Biophys ; 77(4): 319-333, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31559538

RESUMO

Influenza virus is known for its intermittent outbreaks affecting billions of people worldwide. Several neuraminidase inhibitors have been used in practice to overcome this situation. However, advent of new resistant mutants has limited its clinical utilization. In the recent years drug repurposing technique has attained the limelight as it is cost effective and reduces the time consumed for drug discovery. Here, we present multi-dimensional repurposing strategy that integrates the results of ligand-, energy-, receptor cavity, and shape-based pharmacophore algorithm to effectively identify novel drug candidate for influenza. The pharmacophore hypotheses were generated by utilizing the PHASE module of Schrödinger. The generated hypotheses such as AADP, AADDD, and DDRRNH, respectively, for ligand-, e-pharmacophore and receptor cavity based approach alongside shape of oseltamivir were successfully utilized to screen the DrugBank database. Subsequently, these models were evaluated for their differentiating ability using Enrichment calculation. Receiver operating curve and enrichment factors from the analysis indicate that the models possess better capability to screen actives from decoy set of molecules. Eventually, the hits retrieved from different hypotheses were subjected to molecular docking using Glide module of Schrödinger Suite. The results of different algorithms were then combined to eliminate false positive hits and to demonstrate reliable prediction performance than existing approaches. Of note, Pearson's correlation coefficients were calculated to examine the extent of correlation between the glide score and IC50 values. Further, the interaction profile, pharmacokinetic, and pharmacodynamics properties were analyzed for the hit compounds. The results from our analysis showed that alprostadil (DB00770) exhibits better binding affinity toward NA protein than the existing drug molecules. The biological activity of the hit was also predicted using PASS algorithm that renders the antiviral activity of the compound. Further, the results were validated using mutation analysis and molecular dynamic simulation studies. Indeed, this integrative filtering is able to exceed accuracy of other state-of-the-art methods for the drug discovery.


Assuntos
Descoberta de Drogas , Reposicionamento de Medicamentos , Algoritmos , Alprostadil/química , Alprostadil/metabolismo , Alprostadil/uso terapêutico , Antivirais/química , Antivirais/metabolismo , Antivirais/uso terapêutico , Sítios de Ligação , Humanos , Influenza Humana/tratamento farmacológico , Influenza Humana/patologia , Ligantes , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Neuraminidase/química , Neuraminidase/genética , Neuraminidase/metabolismo , Oseltamivir/química , Oseltamivir/metabolismo , Ligação Proteica
20.
Eur J Med Chem ; 183: 111715, 2019 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-31550663

RESUMO

Multiple myeloma (MM) is an incurable hematological malignancy driven by several genetic and epigenetic alterations. The hyperactivation of the Polycomb repressive complex 2 (PRC2), a multi-subunit oncogenic histone methyltransferase, has been implicated in the pathogenesis of this malignancy. Upon protein-protein interaction (PPI) between the catalytic subunit EZH2 and EED, PRC2 primarily methylates lysine 27 of histone H3 (H3K27me3), thus modulating the chromatin structure and inducing transcriptional repression. Herein, we highlight a new mechanism of action that can contribute to explain the anti-tumor activity of hydroxychloroquine (HCQ), an anti-malaric agent also known as autophagy inhibitor. By structural studies, we demonstrate that HCQ inhibits the allosteric binding of PRC2 to EED within the H3K27me3-binding pocket, thus antagonizing the PRC2 catalytic activity. In silico results are compatible with the significant reduction of the H3K27me3 levels in MM cells exerted by HCQ. Overall, these findings disclose a novel epigenetic activity of HCQ with potential implications for its clinical repositioning.


Assuntos
Antineoplásicos , Epigênese Genética/efeitos dos fármacos , Hidroxicloroquina , Complexo Repressor Polycomb 2/antagonistas & inibidores , Antineoplásicos/química , Antineoplásicos/farmacologia , Reposicionamento de Medicamentos , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Histonas/metabolismo , Humanos , Hidroxicloroquina/química , Hidroxicloroquina/farmacologia , Metilação/efeitos dos fármacos
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