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1.
Eur J Med Chem ; 227: 113906, 2022 Jan 05.
Artigo em Inglês | MEDLINE | ID: mdl-34656901

RESUMO

Proteolysis targeting chimeras (PROTACs), which hijack proteins of interest (POIs) and recruit E3 ligases for target degradation via the ubiquitin-proteasome pathway, are a novel drug discovery paradigm that has been widely used as biological tools and medicinal molecules with the potential of clinical application value. To date, a wide variety of small molecule PROTACs have been developed. Importantly, VHL-based PROTACs have emerged to be a promising approach for proteins, including those non-druggable ones, such as transcriptional factors and scaffold proteins. VHL-based PRTOACs have been developed for the treatment of diseases that are difficult to be dealt with by conventional methods, such as radiotherapy, chemotherapy, and small molecule inhibitors. In this review, the recent advances of VHL-based PRTOACs were summarized, and the chances and challenges associated with this area were also highlighted.


Assuntos
Bibliotecas de Moléculas Pequenas/farmacologia , Proteína Supressora de Tumor Von Hippel-Lindau/antagonistas & inibidores , Humanos , Ligantes , Estrutura Molecular , Proteólise/efeitos dos fármacos , Bibliotecas de Moléculas Pequenas/química , Proteína Supressora de Tumor Von Hippel-Lindau/metabolismo
2.
J Exp Med ; 219(1)2022 01 03.
Artigo em Inglês | MEDLINE | ID: mdl-34812843

RESUMO

We describe the discovery of an agonist of the nuclear receptor NR2F1 that specifically activates dormancy programs in malignant cells. The agonist led to a self-regulated increase in NR2F1 mRNA and protein and downstream transcription of a novel dormancy program. This program led to growth arrest of an HNSCC PDX line, human cell lines, and patient-derived organoids in 3D cultures and in vivo. This effect was lost when NR2F1 was knocked out by CRISPR-Cas9. RNA sequencing revealed that agonist treatment induces transcriptional changes associated with inhibition of cell cycle progression and mTOR signaling, metastasis suppression, and induction of a neural crest lineage program. In mice, agonist treatment resulted in inhibition of lung HNSCC metastasis, even after cessation of the treatment, where disseminated tumor cells displayed an NR2F1hi/p27hi/Ki-67lo/p-S6lo phenotype and remained in a dormant single-cell state. Our work provides proof of principle supporting the use of NR2F1 agonists to induce dormancy as a therapeutic strategy to prevent metastasis.


Assuntos
Fator I de Transcrição COUP/agonistas , Carcinoma de Células Escamosas/tratamento farmacológico , Neoplasias de Cabeça e Pescoço/tratamento farmacológico , Neoplasias Pulmonares/prevenção & controle , Bibliotecas de Moléculas Pequenas/farmacologia , Animais , Fator I de Transcrição COUP/genética , Fator I de Transcrição COUP/metabolismo , Carcinoma de Células Escamosas/genética , Carcinoma de Células Escamosas/patologia , Linhagem Celular Tumoral , Feminino , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Células HEK293 , Neoplasias de Cabeça e Pescoço/genética , Neoplasias de Cabeça e Pescoço/patologia , Humanos , Estimativa de Kaplan-Meier , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/secundário , Camundongos Endogâmicos BALB C , Camundongos Nus , Estrutura Molecular , RNA-Seq/métodos , Bibliotecas de Moléculas Pequenas/química , Bibliotecas de Moléculas Pequenas/metabolismo , Ensaios Antitumorais Modelo de Xenoenxerto/métodos
3.
Methods Mol Biol ; 2390: 483-501, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-34731484

RESUMO

The use of artificial intelligence methods in drug safety began in the early 2000s with applications such as predicting bacterial mutagenicity and hERG inhibition. The field has been endlessly expanding ever since and the models have become more complex. These approaches are now integrated into molecule risk assessment processes along with in vitro and in vivo methods. Today, artificial intelligence can be used in every phase of drug discovery and development, from profiling chemical libraries in early discovery, to predicting off-target effects in the mid-discovery phase, to assessing potential mutagenic impurities in development and degradants as part of life cycle management. This chapter provides an overview of artificial intelligence in drug safety and describes its application throughout the entire discovery and development process.


Assuntos
Inteligência Artificial , Descoberta de Drogas , Preparações Farmacêuticas , Bibliotecas de Moléculas Pequenas
4.
Int J Mol Sci ; 22(24)2021 Dec 19.
Artigo em Inglês | MEDLINE | ID: mdl-34948414

RESUMO

Store-operated calcium entry (SOCE) constitutes a fine-tuning mechanism responsible for the replenishment of intracellular stores. Hippocampal SOCE is regulated by store-operated channels (SOC) organized in tripartite complex TRPC6/ORAI2/STIM2. It is suggested that in neurons, SOCE maintains intracellular homeostatic Ca2+ concentration at resting conditions and is needed to support the structure of dendritic spines. Recent evidence suggests that positive modulators of SOC are prospective drug candidates to treat Alzheimer's disease (AD) at early stages. Although STIM2 and ORAI2 are definitely involved in the regulation of nSOC amplitude and a play major role in AD pathogenesis, growing evidence suggest that it is not easy to target these proteins pharmacologically. Existing positive modulators of TRPC6 are unsuitable for drug development due to either bad pharmacokinetics or side effects. Thus, we concentrate the review on perspectives to develop specific nSOC modulators based on available 3D structures of TRPC6, ORAI2, and STIM2. We shortly describe the structural features of existing models and the methods used to prepare them. We provide commonly used steps applied for drug design based on 3D structures of target proteins that might be used to develop novel AD preventing therapy.


Assuntos
Doença de Alzheimer/tratamento farmacológico , Desenho de Fármacos , Proteína ORAI2/metabolismo , Molécula 2 de Interação Estromal/metabolismo , Canal de Cátion TRPC6/metabolismo , Doença de Alzheimer/metabolismo , Animais , Descoberta de Drogas , Humanos , Proteína ORAI2/química , Bibliotecas de Moléculas Pequenas/química , Bibliotecas de Moléculas Pequenas/farmacologia , Molécula 2 de Interação Estromal/química , Sinapses/efeitos dos fármacos , Sinapses/metabolismo , Canal de Cátion TRPC6/química
5.
Cells ; 10(12)2021 12 17.
Artigo em Inglês | MEDLINE | ID: mdl-34944071

RESUMO

Chronic venous diseases, including varicose veins, are characterized by hemodynamic disturbances due to valve defects, venous insufficiency, and orthostatism. Veins are physiologically low shear stress systems, and how altered hemodynamics drives focal endothelial dysfunction and causes venous remodeling is unknown. Here we demonstrate the occurrence of endothelial to mesenchymal transition (EndMT) in human varicose veins. Moreover, the BMP4-pSMAD5 pathway was robustly upregulated in varicose veins. In vitro flow-based assays using human vein, endothelial cells cultured in microfluidic chambers show that even minimal disturbances in shear stress as may occur in early stages of venous insufficiency induce BMP4-pSMAD5-based phenotype switching. Furthermore, low shear stress at uniform laminar pattern does not induce EndMT in venous endothelial cells. Targeting the BMP4-pSMAD5 pathway with small molecule inhibitor LDN193189 reduced SNAI1/2 expression in venous endothelial cells exposed to disturbed flow. TGFß inhibitor SB505124 was less efficient in inhibiting EndMT in venous endothelial cells exposed to disturbed flow. We conclude that disturbed shear stress, even in the absence of any oscillatory flow, induces EndMT in varicose veins via activation of BMP4/pSMAD5-SNAI1/2 signaling. The present findings serve as a rationale for the possible use of small molecular mechanotherapeutics in the management of varicose veins.


Assuntos
Proteína Morfogenética Óssea 4/metabolismo , Células Endoteliais/patologia , Mesoderma/patologia , Transdução de Sinais , Proteína Smad5/metabolismo , Estresse Mecânico , Varizes/metabolismo , Varizes/patologia , Adulto , Idoso , Biomarcadores/metabolismo , Células Endoteliais/efeitos dos fármacos , Feminino , Perfilação da Expressão Gênica , Células Endoteliais da Veia Umbilical Humana/efeitos dos fármacos , Células Endoteliais da Veia Umbilical Humana/metabolismo , Humanos , Masculino , Pessoa de Meia-Idade , Neointima/patologia , Fosforilação/efeitos dos fármacos , Pirazóis/farmacologia , Pirimidinas/farmacologia , Reologia/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , Bibliotecas de Moléculas Pequenas/farmacologia , Fatores de Transcrição da Família Snail/metabolismo , Fator de Crescimento Transformador beta1/metabolismo , Regulação para Cima/efeitos dos fármacos , Adulto Jovem
6.
Nat Commun ; 12(1): 7299, 2021 12 15.
Artigo em Inglês | MEDLINE | ID: mdl-34911927

RESUMO

Huntington's disease (HD) is a hereditary neurodegenerative disorder caused by expansion of cytosine-adenine-guanine (CAG) trinucleotide repeats in the huntingtin (HTT) gene. Consequently, the mutant protein is ubiquitously expressed and drives pathogenesis of HD through a toxic gain-of-function mechanism. Animal models of HD have demonstrated that reducing huntingtin (HTT) protein levels alleviates motor and neuropathological abnormalities. Investigational drugs aim to reduce HTT levels by repressing HTT transcription, stability or translation. These drugs require invasive procedures to reach the central nervous system (CNS) and do not achieve broad CNS distribution. Here, we describe the identification of orally bioavailable small molecules with broad distribution throughout the CNS, which lower HTT expression consistently throughout the CNS and periphery through selective modulation of pre-messenger RNA splicing. These compounds act by promoting the inclusion of a pseudoexon containing a premature termination codon (stop-codon psiExon), leading to HTT mRNA degradation and reduction of HTT levels.


Assuntos
Proteína Huntingtina/genética , Proteína Huntingtina/metabolismo , Doença de Huntington/tratamento farmacológico , Doença de Huntington/genética , Splicing de RNA , Bibliotecas de Moléculas Pequenas/administração & dosagem , Animais , Sistema Nervoso Central/efeitos dos fármacos , Sistema Nervoso Central/metabolismo , Modelos Animais de Doenças , Humanos , Doença de Huntington/metabolismo , Camundongos , Splicing de RNA/efeitos dos fármacos , Estabilidade de RNA/efeitos dos fármacos , Expansão das Repetições de Trinucleotídeos/efeitos dos fármacos
7.
Biomolecules ; 11(12)2021 11 26.
Artigo em Inglês | MEDLINE | ID: mdl-34944420

RESUMO

Lysosomal Storage Diseases are multisystemic disorders determined by genetic variants, which affect the proteins involved in lysosomal function and cellular metabolism. Different therapeutic approaches, which are based on the physiologic mechanisms that regulate lysosomal function, have been proposed for these diseases. Currently, enzyme replacement therapy, gene therapy, or small molecules have been approved or are under clinical development to treat lysosomal storage disorders. The present article reviews the main therapeutic strategies that have been proposed so far, highlighting possible limitations and future perspectives.


Assuntos
Biomarcadores/metabolismo , Doenças por Armazenamento dos Lisossomos/genética , Doenças por Armazenamento dos Lisossomos/terapia , Ensaios Clínicos como Assunto , Terapia de Reposição de Enzimas , Regulação da Expressão Gênica , Terapia Genética , Transplante de Células-Tronco Hematopoéticas , Humanos , Doenças por Armazenamento dos Lisossomos/metabolismo , Bibliotecas de Moléculas Pequenas/uso terapêutico
8.
Biomolecules ; 11(12)2021 11 30.
Artigo em Inglês | MEDLINE | ID: mdl-34944433

RESUMO

The proteasome system is a large and complex molecular machinery responsible for the degradation of misfolded, damaged, and redundant cellular proteins. When proteasome function is impaired, unwanted proteins accumulate, which can lead to several diseases including age-related and neurodegenerative diseases. Enhancing proteasome-mediated substrate degradation with small molecules may therefore be a valuable strategy for the treatment of various neurodegenerative diseases such as Parkinson's, Alzheimer's, and Huntington's diseases. In this review, we discuss the structure of proteasome and how proteasome's proteolytic activity is associated with aging and various neurodegenerative diseases. We also summarize various classes of compounds that are capable of enhancing, directly or indirectly, proteasome-mediated protein degradation.


Assuntos
Envelhecimento/metabolismo , Doenças Neurodegenerativas/metabolismo , Complexo de Endopeptidases do Proteassoma/metabolismo , Bibliotecas de Moléculas Pequenas/farmacologia , Humanos , Inibidores de Proteassoma/farmacologia , Dobramento de Proteína , Proteólise/efeitos dos fármacos
9.
Biomolecules ; 11(12)2021 11 30.
Artigo em Inglês | MEDLINE | ID: mdl-34944436

RESUMO

The 'inverse problem' of mass spectrometric molecular identification ('given a mass spectrum, calculate/predict the 2D structure of the molecule whence it came') is largely unsolved, and is especially acute in metabolomics where many small molecules remain unidentified. This is largely because the number of experimentally available electrospray mass spectra of small molecules is quite limited. However, the forward problem ('calculate a small molecule's likely fragmentation and hence at least some of its mass spectrum from its structure alone') is much more tractable, because the strengths of different chemical bonds are roughly known. This kind of molecular identification problem may be cast as a language translation problem in which the source language is a list of high-resolution mass spectral peaks and the 'translation' a representation (for instance in SMILES) of the molecule. It is thus suitable for attack using the deep neural networks known as transformers. We here present MassGenie, a method that uses a transformer-based deep neural network, trained on ~6 million chemical structures with augmented SMILES encoding and their paired molecular fragments as generated in silico, explicitly including the protonated molecular ion. This architecture (containing some 400 million elements) is used to predict the structure of a molecule from the various fragments that may be expected to be observed when some of its bonds are broken. Despite being given essentially no detailed nor explicit rules about molecular fragmentation methods, isotope patterns, rearrangements, neutral losses, and the like, MassGenie learns the effective properties of the mass spectral fragment and valency space, and can generate candidate molecular structures that are very close or identical to those of the 'true' molecules. We also use VAE-Sim, a previously published variational autoencoder, to generate candidate molecules that are 'similar' to the top hit. In addition to using the 'top hits' directly, we can produce a rank order of these by 'round-tripping' candidate molecules and comparing them with the true molecules, where known. As a proof of principle, we confine ourselves to positive electrospray mass spectra from molecules with a molecular mass of 500Da or lower, including those in the last CASMI challenge (for which the results are known), getting 49/93 (53%) precisely correct. The transformer method, applied here for the first time to mass spectral interpretation, works extremely effectively both for mass spectra generated in silico and on experimentally obtained mass spectra from pure compounds. It seems to act as a Las Vegas algorithm, in that it either gives the correct answer or simply states that it cannot find one. The ability to create and to 'learn' millions of fragmentation patterns in silico, and therefrom generate candidate structures (that do not have to be in existing libraries) directly, thus opens up entirely the field of de novo small molecule structure prediction from experimental mass spectra.


Assuntos
Metabolômica/métodos , Bibliotecas de Moléculas Pequenas/análise , Algoritmos , Aprendizado Profundo , Espectrometria de Massas , Estrutura Molecular
10.
J Med Chem ; 64(24): 17656-17689, 2021 12 23.
Artigo em Inglês | MEDLINE | ID: mdl-34905377

RESUMO

Neuroinflammation is an adaptive response of the central nervous system to diverse potentially injurious stimuli, which is closely associated with neurodegeneration and typically characterized by activation of microglia and astrocytes. As a noninvasive and translational molecular imaging tool, positron emission tomography (PET) could provide a better understanding of neuroinflammation and its role in neurodegenerative diseases. Ligands to translator protein (TSPO), a putative marker of neuroinflammation, have been the most commonly studied in this context, but they suffer from serious limitations. Herein we present a repertoire of different structural chemotypes and novel PET ligand design for classical and emerging neuroinflammatory targets beyond TSPO. We believe that this Perspective will support multidisciplinary collaborations in academic and industrial institutions working on neuroinflammation and facilitate the progress of neuroinflammation PET probe development for clinical use.


Assuntos
/diagnóstico por imagem , Tomografia por Emissão de Pósitrons/métodos , Compostos Radiofarmacêuticos/química , Receptores de GABA/química , Bibliotecas de Moléculas Pequenas/química , Animais , Humanos
11.
Biomolecules ; 11(12)2021 11 24.
Artigo em Inglês | MEDLINE | ID: mdl-34944403

RESUMO

The pyrazolyl-urea Gege3 molecule has shown interesting antiangiogenic effects in the tumor contest. Here, we have studied the role of this compound as interfering with endothelial cells activation in response to the paracrine effects of annexin A1 (ANXA1), known to be involved in promoting tumor progression. ANXA1 has been analyzed in the extracellular environment once secreted through microvesicles (EVs) by pancreatic cancer (PC) cells. Particularly, Gege3 has been able to notably prevent the effects of Ac2-26, the ANXA1 mimetic peptide, and of PC-derived EVs on endothelial cells motility, angiogenesis, and calcium release. Furthermore, this compound also inhibited the translocation of ANXA1 to the plasma membrane, otherwise induced by the same ANXA1-dependent extracellular stimuli. Moreover, these effects have been mediated by the indirect inhibition of protein kinase Cα (PKCα), which generally promotes the phosphorylation of ANXA1 on serine 27. Indeed, by the subtraction of intracellular calcium levels, the pathway triggered by PKCα underwent a strong inhibition leading to the following impediment to the ANXA1 localization at the plasma membrane, as revealed by confocal and cytofluorimetry analysis. Thus, Gege3 appeared an attractive molecule able to prevent the paracrine effects of PC cells deriving ANXA1 in the tumor microenvironment.


Assuntos
Anexina A1/metabolismo , Regulação para Baixo , Vesículas Extracelulares/metabolismo , Neoplasias Pancreáticas/metabolismo , Bibliotecas de Moléculas Pequenas/farmacologia , Ureia/química , Anexina A1/farmacologia , Cálcio/metabolismo , Linhagem Celular Tumoral , Membrana Celular/metabolismo , Movimento Celular/efeitos dos fármacos , Vesículas Extracelulares/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Células Endoteliais da Veia Umbilical Humana , Humanos , Neoplasias Pancreáticas/tratamento farmacológico , Comunicação Parácrina/efeitos dos fármacos , Peptídeos/farmacologia , Fosforilação/efeitos dos fármacos , Transporte Proteico/efeitos dos fármacos , Bibliotecas de Moléculas Pequenas/química , Microambiente Tumoral/efeitos dos fármacos
12.
Nat Commun ; 12(1): 7190, 2021 12 14.
Artigo em Inglês | MEDLINE | ID: mdl-34907165

RESUMO

Interrogation of cellular metabolism with high-throughput screening approaches can unravel contextual biology and identify cancer-specific metabolic vulnerabilities. To systematically study the consequences of distinct metabolic perturbations, we assemble a comprehensive metabolic drug library (CeMM Library of Metabolic Drugs; CLIMET) covering 243 compounds. We, next, characterize it phenotypically in a diverse panel of myeloid leukemia cell lines and primary patient cells. Analysis of the drug response profiles reveals that 77 drugs affect cell viability, with the top effective compounds targeting nucleic acid synthesis, oxidative stress, and the PI3K/mTOR pathway. Clustering of individual drug response profiles stratifies the cell lines into five functional groups, which link to specific molecular and metabolic features. Mechanistic characterization of selective responses to the PI3K inhibitor pictilisib, the fatty acid synthase inhibitor GSK2194069, and the SLC16A1 inhibitor AZD3965, bring forth biomarkers of drug response. Phenotypic screening using CLIMET represents a valuable tool to probe cellular metabolism and identify metabolic dependencies at large.


Assuntos
Leucemia Mieloide/metabolismo , Bibliotecas de Moléculas Pequenas/metabolismo , Bibliotecas de Moléculas Pequenas/farmacologia , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Sobrevivência Celular/efeitos dos fármacos , Análise por Conglomerados , Ácidos Graxos/biossíntese , Genótipo , Humanos , Leucemia Mieloide/genética , Leucemia Mieloide/patologia , Transportadores de Ácidos Monocarboxílicos/genética , Fenótipo , Fosfatidilinositol 3-Quinase/metabolismo , Inibidores de Fosfoinositídeo-3 Quinase/metabolismo , Inibidores de Fosfoinositídeo-3 Quinase/farmacologia , Pirimidinonas/metabolismo , Pirimidinonas/farmacologia , Pirrolidinas/metabolismo , Pirrolidinas/farmacologia , Transdução de Sinais , Bibliotecas de Moléculas Pequenas/classificação , Simportadores/genética , Análise de Sistemas , Tiofenos/metabolismo , Tiofenos/farmacologia , Triazóis/metabolismo , Triazóis/farmacologia , Células Tumorais Cultivadas
13.
Int J Mol Sci ; 22(24)2021 Dec 14.
Artigo em Inglês | MEDLINE | ID: mdl-34948208

RESUMO

Recurrence and metastasis remain major obstacles in colorectal cancer (CRC) treatment. Recent studies suggest that a small subpopulation of cells with a self-renewal ability, called cancer stem-like cells (CSCs), promotes recurrence and metastasis in CRC. Unfortunately, no CSC inhibitor has been demonstrated to be more effective than existing chemotherapeutic drugs, resulting in a significant unmet need for effective CRC therapies. In this study, transcriptomic profiling of metastatic tumors from CRC patients revealed significant upregulation in the Wnt pathway and stemness genes. Thus, we examined the therapeutic effect of the small-molecule Wnt inhibitor ICG-001 on cancer stemness and metastasis. The ICG-001 treatment efficiently attenuated self-renewal activity and metastatic potential. Mechanistically, myeloid ecotropic viral insertion site 1 (MEIS1) was identified as a target gene of ICG-001 that is transcriptionally regulated by Wnt signaling. A series of functional analyses revealed that MEIS1 enhanced the CSC behavior and metastatic potential of the CRC cells. Collectively, our findings suggest that ICG-001 efficiently inhibits CRC stemness and metastasis by suppressing MEIS1 expression. These results provide a basis for the further clinical investigation of ICG-001 as a targeted therapy for CSCs, opening a new avenue for the development of novel Wnt inhibitors for the treatment of CRC metastasis.


Assuntos
Compostos Bicíclicos Heterocíclicos com Pontes/farmacologia , Neoplasias Colorretais/tratamento farmacológico , Proteína Meis1/metabolismo , Células-Tronco Neoplásicas/efeitos dos fármacos , Pirimidinonas/farmacologia , Bibliotecas de Moléculas Pequenas/farmacologia , Via de Sinalização Wnt/efeitos dos fármacos , Animais , Linhagem Celular Tumoral , Neoplasias Colorretais/metabolismo , Perfilação da Expressão Gênica/métodos , Células HCT116 , Células HT29 , Humanos , Masculino , Camundongos , Camundongos Endogâmicos NOD , Transcrição Genética/efeitos dos fármacos
14.
J Chem Inf Model ; 61(11): 5458-5468, 2021 11 22.
Artigo em Inglês | MEDLINE | ID: mdl-34669418

RESUMO

A new methodology for classifying fragment combinations and characterizing pseudonatural products (PNPs) is described. The source code is based on open-source tools and is organized as a Python package. Tasks can be executed individually or within the context of scalable, robust workflows. First, structures are standardized and duplicate entries are filtered out. Then, molecules are probed for the presence of predefined fragments. For molecules with more than one match, fragment combinations are classified. The algorithm considers the pairwise relative position of fragments within the molecule (fused atoms, linkers, intermediary rings), resulting in 18 different possible fragment combination categories. Finally, all combinations for a given molecule are assembled into a fragment combination graph, with fragments as nodes and combination types as edges. This workflow was applied to characterize PNPs in the ChEMBL database via comparison of fragment combination graphs with natural product (NP) references, represented by the Dictionary of Natural Products. The Murcko fragments extracted from 2000 structures previously described were used to define NP fragments. The results indicate that ca. 23% of the biologically relevant compounds listed in ChEMBL comply to the PNP definition and that, therefore, PNPs occur frequently among known biologically relevant small molecules. The majority (>95%) of PNPs contain two to four fragments, mainly (>95%) distributed in five different combination types. These findings may provide guidance for the design of new PNPs.


Assuntos
Produtos Biológicos , Bibliotecas de Moléculas Pequenas , Algoritmos , Bases de Dados Factuais , Software
15.
Arch Biochem Biophys ; 713: 109059, 2021 11 30.
Artigo em Inglês | MEDLINE | ID: mdl-34673001

RESUMO

Approved mAbs that block the protein-protein interaction (PPI) interface of the PD-1/PD-L1 immune checkpoint axis have led to significant improvements in cancer treatment. Despite having drawbacks of mAbs only few a compounds are reported till date against this axis. Inhibiting PPIs using small molecules has emerged as a significant therapeutic opportunity, demanding for the identification of drug-like molecules at an accelerated pace under the hit-to-lead campaigns. Due to the PD-L1's cross-talk with PD-1/CD80 and its overexpression on cancer cells, as well as the availability of its crystal structures with small molecules, it is an enticing therapeutic target for structure-assisted small molecule design. Furthermore, the selection of chemical databases enriched with focused designing for PPI interfaces is crucial. Therefore, in this study we have utilized the Asinex signature library for structure-assisted virtual screening to find the potential PD-L1 inhibitors by targeting the cryptic PD-L1 interface, followed by induced fit docking for pose refinements in the pocket. The obtained hits were then subjected to interaction fingerprinting and ligand-based drug-likeness investigations in order to evaluate and analyze their drug-like qualities (ADME). Twelve compounds qualified for molecular dynamics simulations, followed by thermodynamic calculations for evaluation of their stability and energetics inside the pocket. Two novel compounds with different chemical moieties have been identified that are consistent throughout the simulation, mimicking the interactions and binding energies with BMS-1166. These compounds appear as potential therapeutic candidates to be explored experimentally, thereby paving the way for the development of novel leads as immunomodulators.


Assuntos
Antígeno B7-H1/antagonistas & inibidores , Antígeno B7-H1/metabolismo , Inibidores de Checkpoint Imunológico/metabolismo , Bibliotecas de Moléculas Pequenas/metabolismo , Sequência de Aminoácidos , Antígeno B7-H1/química , Sítios de Ligação , Humanos , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Ligação Proteica , Termodinâmica
16.
Molecules ; 26(20)2021 Oct 12.
Artigo em Inglês | MEDLINE | ID: mdl-34684735

RESUMO

In continuation of our previous effort, different in silico selection methods were applied to 310 naturally isolated metabolites that exhibited antiviral potentialities before. The applied selection methods aimed to pick the most relevant inhibitor of SARS-CoV-2 nsp10. At first, a structural similarity study against the co-crystallized ligand, S-Adenosyl Methionine (SAM), of SARS-CoV-2 nonstructural protein (nsp10) (PDB ID: 6W4H) was carried out. The similarity analysis culled 30 candidates. Secondly, a fingerprint study against SAM preferred compounds 44, 48, 85, 102, 105, 182, 220, 221, 282, 284, 285, 301, and 302. The docking studies picked 48, 182, 220, 221, and 284. While the ADMET analysis expected the likeness of the five candidates to be drugs, the toxicity study preferred compounds 48 and 182. Finally, a density-functional theory (DFT) study suggested vidarabine (182) to be the most relevant SARS-Cov-2 nsp10 inhibitor.


Assuntos
Antivirais/química , Produtos Biológicos/química , SARS-CoV-2/metabolismo , Proteínas Virais Reguladoras e Acessórias/antagonistas & inibidores , Antivirais/metabolismo , Antivirais/uso terapêutico , Sítios de Ligação , Produtos Biológicos/metabolismo , Produtos Biológicos/uso terapêutico , COVID-19/tratamento farmacológico , COVID-19/patologia , Teoria da Densidade Funcional , Humanos , Ligantes , Simulação de Acoplamento Molecular , S-Adenosilmetionina/química , S-Adenosilmetionina/metabolismo , SARS-CoV-2/isolamento & purificação , Bibliotecas de Moléculas Pequenas/química , Bibliotecas de Moléculas Pequenas/metabolismo , Bibliotecas de Moléculas Pequenas/uso terapêutico , Vidarabina/química , Vidarabina/metabolismo , Vidarabina/uso terapêutico , Proteínas Virais Reguladoras e Acessórias/metabolismo
17.
Cells ; 10(10)2021 10 16.
Artigo em Inglês | MEDLINE | ID: mdl-34685753

RESUMO

Cancer stem cells, in contrast to their more differentiated daughter cells, can endure genotoxic insults, escape apoptosis, and cause tumor recurrence. Understanding how normal adult stem cells survive and go to quiescence may help identify druggable pathways that cancer stem cells have co-opted. In this study, we utilize a genetically tractable model for stem cell survival in the Drosophila gonad to screen drug candidates and probe chemical-genetic interactions. Our study employs three levels of small molecule screening: (1) a medium-throughput primary screen in male germline stem cells (GSCs), (2) a secondary screen with irradiation and protein-constrained food in female GSCs, and (3) a tertiary screen in breast cancer organoids in vitro. Herein, we uncover a series of small molecule drug candidates that may sensitize cancer stem cells to apoptosis. Further, we have assessed these small molecules for chemical-genetic interactions in the germline and identified the NF-κB pathway as an essential and druggable pathway in GSC quiescence and viability. Our study demonstrates the power of the Drosophila stem cell niche as a model system for targeted drug discovery.


Assuntos
Apoptose/genética , Drosophila melanogaster/genética , Testes Genéticos , Células Germinativas/metabolismo , Preparações Farmacêuticas/metabolismo , Bibliotecas de Moléculas Pequenas/farmacologia , Células-Tronco/metabolismo , Animais , Apoptose/efeitos dos fármacos , Neoplasias da Mama/patologia , Drosophila melanogaster/efeitos dos fármacos , Feminino , Células Germinativas/efeitos dos fármacos , Humanos , Células MCF-7 , Masculino , Organoides/efeitos dos fármacos , Organoides/patologia , Ovário/citologia , Ovário/efeitos dos fármacos , Interferência de RNA , Células-Tronco/efeitos dos fármacos , Testículo/citologia , Testículo/efeitos dos fármacos
18.
Nat Commun ; 12(1): 6150, 2021 10 22.
Artigo em Inglês | MEDLINE | ID: mdl-34686672

RESUMO

Cell-based transcriptional reporters are invaluable in high-throughput compound and CRISPR screens for identifying compounds or genes that can impact a pathway of interest. However, many transcriptional reporters have weak activities and transient responses. This can result in overlooking therapeutic targets and compounds that are difficult to detect, necessitating the resource-consuming process of running multiple screens at various timepoints. Here, we present RADAR, a digitizer circuit for amplifying reporter activity and retaining memory of pathway activation. Reporting on the AP-1 pathway, our circuit identifies compounds with known activity against PKC-related pathways and shows an enhanced dynamic range with improved sensitivity compared to a classical reporter in compound screens. In the first genome-wide pooled CRISPR screen for the AP-1 pathway, RADAR identifies canonical genes from the MAPK and PKC pathways, as well as non-canonical regulators. Thus, our scalable system highlights the benefit and versatility of using genetic circuits in large-scale cell-based screening.


Assuntos
Genômica/métodos , Ensaios de Triagem em Larga Escala/métodos , Sistemas CRISPR-Cas , Genes Reporter , Humanos , Regiões Promotoras Genéticas , Bibliotecas de Moléculas Pequenas/farmacologia , Fatores de Transcrição/química , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo
19.
Int J Mol Sci ; 22(19)2021 Oct 06.
Artigo em Inglês | MEDLINE | ID: mdl-34639142

RESUMO

G-quadruplexes are four-stranded nucleic acid secondary structures of biological significance and have emerged as an attractive drug target. The G4 formed in the MYC promoter (MycG4) is one of the most studied small-molecule targets, and a model system for parallel structures that are prevalent in promoter DNA G4s and RNA G4s. Molecular docking has become an essential tool in structure-based drug discovery for protein targets, and is also increasingly applied to G4 DNA. However, DNA, and in particular G4, binding sites differ significantly from protein targets. Here we perform the first systematic evaluation of four commonly used docking programs (AutoDock Vina, DOCK 6, Glide, and RxDock) for G4 DNA-ligand binding pose prediction using four small molecules whose complex structures with the MycG4 have been experimentally determined in solution. The results indicate that there are considerable differences in the performance of the docking programs and that DOCK 6 with GB/SA rescoring performs better than the other programs. We found that docking accuracy is mainly limited by the scoring functions. The study shows that current docking programs should be used with caution to predict G4 DNA-small molecule binding modes.


Assuntos
DNA/metabolismo , Quadruplex G , Simulação de Acoplamento Molecular , Proteínas Proto-Oncogênicas c-myc/metabolismo , Bibliotecas de Moléculas Pequenas/metabolismo , Software , Sítios de Ligação , DNA/química , DNA/genética , Humanos , Ligantes , Proteínas Proto-Oncogênicas c-myc/genética
20.
Int J Mol Sci ; 22(19)2021 Oct 06.
Artigo em Inglês | MEDLINE | ID: mdl-34639140

RESUMO

Amyloid beta (Aß) oligomers are the most neurotoxic aggregates causing neuronal death and cognitive damage. A detailed elucidation of the aggregation pathways from oligomers to fibril formation is crucial to develop therapeutic strategies for Alzheimer's disease (AD). Although experimental techniques rely on the measure of time- and space-average properties, they face severe difficulties in the investigation of Aß peptide aggregation due to their intrinsically disorder character. Computer simulation is a tool that allows tracing the molecular motion of molecules; hence it complements Aß experiments, as it allows to explore the binding mechanism between metal ions and Aß oligomers close to the cellular membrane at the atomic resolution. In this context, integrated studies of experiments and computer simulations can assist in mapping the complete pathways of aggregation and toxicity of Aß peptides. Aß oligomers are disordered proteins, and due to a rapid exploration of their intrinsic conformational space in real-time, they are challenging therapeutic targets. Therefore, no good drug candidate could have been identified for clinical use. Our previous investigations identified two small molecules, M30 (2-Octahydroisoquinolin-2(1H)-ylethanamine) and Gabapentin, capable of Aß binding and inhibiting molecular aggregation, synaptotoxicity, intracellular calcium signaling, cellular toxicity and memory losses induced by Aß. Thus, we recommend these molecules as novel candidates to assist anti-AD drug discovery in the near future. This review discusses the most recent research investigations about the Aß dynamics in water, close contact with cell membranes, and several therapeutic strategies to remove plaque formation.


Assuntos
Doença de Alzheimer/prevenção & controle , Peptídeos beta-Amiloides/metabolismo , Ansiolíticos/uso terapêutico , Gabapentina/uso terapêutico , Hidroxiquinolinas/uso terapêutico , Bibliotecas de Moléculas Pequenas/uso terapêutico , Doença de Alzheimer/metabolismo , Doença de Alzheimer/patologia , Animais , Humanos
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