RESUMO
Ageing of the immune system, or immunosenescence, contributes to the morbidity and mortality of the elderly1,2. To define the contribution of immune system ageing to organism ageing, here we selectively deleted Ercc1, which encodes a crucial DNA repair protein3,4, in mouse haematopoietic cells to increase the burden of endogenous DNA damage and thereby senescence5-7 in the immune system only. We show that Vav-iCre+/-;Ercc1-/fl mice were healthy into adulthood, then displayed premature onset of immunosenescence characterized by attrition and senescence of specific immune cell populations and impaired immune function, similar to changes that occur during ageing in wild-type mice8-10. Notably, non-lymphoid organs also showed increased senescence and damage, which suggests that senescent, aged immune cells can promote systemic ageing. The transplantation of splenocytes from Vav-iCre+/-;Ercc1-/fl or aged wild-type mice into young mice induced senescence in trans, whereas the transplantation of young immune cells attenuated senescence. The treatment of Vav-iCre+/-;Ercc1-/fl mice with rapamycin reduced markers of senescence in immune cells and improved immune function11,12. These data demonstrate that an aged, senescent immune system has a causal role in driving systemic ageing and therefore represents a key therapeutic target to extend healthy ageing.
Assuntos
Envelhecimento/imunologia , Envelhecimento/fisiologia , Sistema Imunitário/imunologia , Sistema Imunitário/fisiologia , Imunossenescência/imunologia , Imunossenescência/fisiologia , Especificidade de Órgãos/imunologia , Especificidade de Órgãos/fisiologia , Envelhecimento/efeitos dos fármacos , Envelhecimento/patologia , Animais , Dano ao DNA/imunologia , Dano ao DNA/fisiologia , Reparo do DNA/imunologia , Reparo do DNA/fisiologia , Proteínas de Ligação a DNA/genética , Endonucleases/genética , Feminino , Envelhecimento Saudável/imunologia , Envelhecimento Saudável/fisiologia , Homeostase/imunologia , Homeostase/fisiologia , Sistema Imunitário/efeitos dos fármacos , Imunossenescência/efeitos dos fármacos , Masculino , Camundongos , Especificidade de Órgãos/efeitos dos fármacos , Rejuvenescimento , Sirolimo/farmacologia , Baço/citologia , Baço/transplanteRESUMO
Drug discovery and development constitute a laborious and costly undertaking. The success of a drug hinges not only good efficacy but also acceptable absorption, distribution, metabolism, elimination, and toxicity (ADMET) properties. Overall, up to 50% of drug development failures have been contributed from undesirable ADMET profiles. As a multiple parameter objective, the optimization of the ADMET properties is extremely challenging owing to the vast chemical space and limited human expert knowledge. In this study, a freely available platform called Chemical Molecular Optimization, Representation and Translation (ChemMORT) is developed for the optimization of multiple ADMET endpoints without the loss of potency (https://cadd.nscc-tj.cn/deploy/chemmort/). ChemMORT contains three modules: Simplified Molecular Input Line Entry System (SMILES) Encoder, Descriptor Decoder and Molecular Optimizer. The SMILES Encoder can generate the molecular representation with a 512-dimensional vector, and the Descriptor Decoder is able to translate the above representation to the corresponding molecular structure with high accuracy. Based on reversible molecular representation and particle swarm optimization strategy, the Molecular Optimizer can be used to effectively optimize undesirable ADMET properties without the loss of bioactivity, which essentially accomplishes the design of inverse QSAR. The constrained multi-objective optimization of the poly (ADP-ribose) polymerase-1 inhibitor is provided as the case to explore the utility of ChemMORT.
Assuntos
Aprendizado Profundo , Humanos , Desenvolvimento de Medicamentos , Descoberta de Drogas , Inibidores de Poli(ADP-Ribose) PolimerasesRESUMO
Machine learning-based scoring functions (MLSFs) have become a very favorable alternative to classical scoring functions because of their potential superior screening performance. However, the information of negative data used to construct MLSFs was rarely reported in the literature, and meanwhile the putative inactive molecules recorded in existing databases usually have obvious bias from active molecules. Here we proposed an easy-to-use method named AMLSF that combines active learning using negative molecular selection strategies with MLSF, which can iteratively improve the quality of inactive sets and thus reduce the false positive rate of virtual screening. We chose energy auxiliary terms learning as the MLSF and validated our method on eight targets in the diverse subset of DUD-E. For each target, we screened the IterBioScreen database by AMLSF and compared the screening results with those of the four control models. The results illustrate that the number of active molecules in the top 1000 molecules identified by AMLSF was significantly higher than those identified by the control models. In addition, the free energy calculation results for the top 10 molecules screened out by the AMLSF, null model and control models based on DUD-E also proved that more active molecules can be identified, and the false positive rate can be reduced by AMLSF.
Assuntos
Proteínas , Proteínas/metabolismo , Bases de Dados Factuais , Ligantes , Simulação de Acoplamento Molecular , Ligação ProteicaRESUMO
Osteoarthritis (OA) pain is often associated with the expression of tumor necrosis factor alpha (TNF-α), suggesting that TNF-α is one of the main contributing factors that cause inflammation, pain, and OA pathology. Thus, inhibition of TNF-α could potentially improve OA symptoms and slow disease progression. Anti-TNF-α treatments with antibodies, however, require multiple treatments and cannot entirely block TNF-α. TNF-α-induced protein 8-like 2 (TIPE2) was found to regulate the immune system's homeostasis and inflammation through different mechanisms from anti-TNF-α therapies. With a single treatment of adeno-associated virus (AAV)-TIPE2 gene delivery in the accelerated aging Zmpste24-/- (Z24-/-) mouse model, we found differences in Safranin O staining intensity within the articular cartilage (AC) region of the knee between TIPE2-treated mice and control mice. The glycosaminoglycan content (orange-red) was degraded in the Z24-/- cartilage while shown to be restored in the TIPE2-treated Z24-/- cartilage. We also observed that chondrocytes in Z24-/- mice exhibited a variety of senescent-associated phenotypes. Treatment with TIPE2 decreased TNF-α-positive cells, ß-galactosidase (ß-gal) activity, and p16 expression seen in Z24-/- mice. Our study demonstrated that AAV-TIPE2 gene delivery effectively blocked TNF-α-induced inflammation and senescence, resulting in the prevention or delay of knee OA in our accelerated aging Z24-/- mouse model.
RESUMO
Osteoarthritis (OA) is a dynamic condition characterized by cartilage damage and synovial inflammation. Ozone (O3) shows potential therapeutic effects owing to its anti-inflammatory properties; however, its high reactivity and short half-life substantially limit its effectiveness in OA treatment. In this study, an ozone-rich thermosensitive nanocomposite hydrogel loaded with D-mannose is developed for OA treatment. Briefly, O3 is encapsulated in nanoparticles (NPs) composed of perfluorotributylamine and fluorinated hyaluronic acid to improve its stability. Next, D-mannose is conjugated with α-amino of the hydroxypropyl chitin (HPCH) via Schiff base to prepare MHPCH. These nanoparticles are encapsulated in MHPCH to produce O3 NPs@MHPCH. In vitro cell experiments demonstrate that the O3 NPs@MHPCH treatment significantly reduced VEGF and inflammation levels, accompanied by a decrease in inflammatory factors such as IL-1ß, IL-6, TNF-α, and iNOS. Furthermore, O3 NPs@MHPCH promotes the expression of collagen II and aggrecan and stimulates chondrocyte proliferation. Additionally, in vivo studies show that O3 NPs@MHPCH significantly alleviated OA by reducing synovial inflammation, cartilage destruction, and subchondral bone remodeling. O3 NPs@MHPCH offers a promising option for improving the efficacy of O3 therapy and reducing the risk of synovial inflammation and cartilage degeneration in OA.
Assuntos
Anti-Inflamatórios , Hidrogéis , Manose , Nanocompostos , Osteoartrite , Ozônio , Nanocompostos/química , Osteoartrite/tratamento farmacológico , Osteoartrite/patologia , Animais , Ozônio/química , Anti-Inflamatórios/farmacologia , Anti-Inflamatórios/química , Anti-Inflamatórios/uso terapêutico , Hidrogéis/química , Manose/química , Cartilagem/efeitos dos fármacos , Cartilagem/patologia , Camundongos , Masculino , Injeções , Condrócitos/efeitos dos fármacos , Condrócitos/metabolismoRESUMO
BACKGROUND: Triple-negative breast cancer (TNBC) is a recurrent, heterogeneous, and invasive form of breast cancer. The treatment of TNBC patients with paclitaxel and fluorouracil in a sequential manner has shown promising outcomes. However, it is challenging to deliver these chemotherapeutic agents sequentially to TNBC tumors. We aim to explore a precision therapy strategy for TNBC through the sequential delivery of paclitaxel and fluorouracil. METHODS: We developed a dual chemo-loaded aptamer with redox-sensitive caged paclitaxel for rapid release and non-cleavable caged fluorouracil for slow release. The binding affinity to the target protein was validated using Enzyme-linked oligonucleotide assays and Surface plasmon resonance assays. The targeting and internalization abilities into tumors were confirmed using Flow cytometry assays and Confocal microscopy assays. The inhibitory effects on TNBC progression were evaluated by pharmacological studies in vitro and in vivo. RESULTS: Various redox-responsive aptamer-paclitaxel conjugates were synthesized. Among them, AS1411-paclitaxel conjugate with a thioether linker (ASP) exhibited high anti-proliferation ability against TNBC cells, and its targeting ability was further improved through fluorouracil modification. The fluorouracil modified AS1411-paclitaxel conjugate with a thioether linker (FASP) exhibited effective targeting of TNBC cells and significantly improved the inhibitory effects on TNBC progression in vitro and in vivo. CONCLUSIONS: This study successfully developed fluorouracil-modified AS1411-paclitaxel conjugates with a thioether linker for targeted combination chemotherapy in TNBC. These conjugates demonstrated efficient recognition of TNBC cells, enabling targeted delivery and controlled release of paclitaxel and fluorouracil. This approach resulted in synergistic antitumor effects and reduced toxicity in vivo. However, challenges related to stability, immunogenicity, and scalability need to be further investigated for future translational applications.
Assuntos
Aptâmeros de Nucleotídeos , Preparações de Ação Retardada , Liberação Controlada de Fármacos , Fluoruracila , Nucleolina , Paclitaxel , Fosfoproteínas , Proteínas de Ligação a RNA , Neoplasias de Mama Triplo Negativas , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Neoplasias de Mama Triplo Negativas/patologia , Aptâmeros de Nucleotídeos/farmacologia , Aptâmeros de Nucleotídeos/química , Humanos , Paclitaxel/uso terapêutico , Paclitaxel/farmacologia , Linhagem Celular Tumoral , Animais , Feminino , Fluoruracila/farmacologia , Fluoruracila/uso terapêutico , Proteínas de Ligação a RNA/metabolismo , Fosfoproteínas/metabolismo , Oligodesoxirribonucleotídeos/farmacologia , Oligodesoxirribonucleotídeos/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Camundongos Nus , Ensaios Antitumorais Modelo de Xenoenxerto , Proliferação de Células/efeitos dos fármacos , Oxirredução/efeitos dos fármacos , Camundongos Endogâmicos BALB CRESUMO
The critical role of the gut microbiome in gastrointestinal cancers is becoming increasingly clear. Imbalances in the gut microbial community, referred to as dysbiosis, are linked to increased risks for various forms of gastrointestinal cancers. Pathogens like Fusobacterium and Helicobacter pylori relate to the onset of esophageal and gastric cancers, respectively, while microbes such as Porphyromonas gingivalis and Clostridium species have been associated with a higher risk of pancreatic cancer. In colorectal cancer, bacteria such as Fusobacterium nucleatum are known to stimulate the growth of tumor cells and trigger cancer-promoting pathways. On the other hand, beneficial microbes like Bifidobacteria offer a protective effect, potentially inhibiting the development of gastrointestinal cancers. The potential for therapeutic interventions that manipulate the gut microbiome is substantial, including strategies to engineer anti-tumor metabolites and employ microbiota-based treatments. Despite the progress in understanding the influence of the microbiome on gastrointestinal cancers, significant challenges remain in identifying and understanding the precise contributions of specific microbial species and their metabolic products. This knowledge is essential for leveraging the role of the gut microbiome in the development of precise diagnostics and targeted therapies for gastrointestinal cancers.
Assuntos
Disbiose , Microbioma Gastrointestinal , Neoplasias Gastrointestinais , Humanos , Neoplasias Gastrointestinais/microbiologia , Neoplasias Gastrointestinais/diagnóstico , Neoplasias Gastrointestinais/metabolismo , Neoplasias Gastrointestinais/terapia , Animais , Medicina de PrecisãoRESUMO
Synovitis is characterized by a distinctmetabolic profile featuring the accumulation of lactate, a byproduct of cellular metabolism within inflamed joints. This study reveals that the activation of the CD31 signal by lactate instigates a metabolic shift, specifically initiating endothelial cell autophagy. This adaptive process plays a pivotal role in fulfilling the augmented energy and biomolecule demands associated with the formation of new blood vessels in the synovium of Rheumatoid Arthritis (RA). Additionally, the amino acid substitutions in the CD31 cytoplasmic tail at the Y663F and Y686F sites of the immunoreceptor tyrosine-based inhibitory motifs (ITIM) alleviate RA. Mechanistically, this results in the downregulation of glycolysis and autophagy pathways. These findings significantly advance our understanding of potential therapeutic strategies for modulating these processes in synovitis and, potentially, other autoimmune diseases.
Assuntos
Artrite Reumatoide , Autofagia , Artrite Reumatoide/metabolismo , Artrite Reumatoide/patologia , Animais , Humanos , Glicólise , Masculino , Membrana Sinovial/metabolismo , Ácido Láctico/metabolismo , Células Endoteliais/metabolismoRESUMO
Drug-drug interaction (DDI) can trigger many adverse effects in patients and has emerged as a threat to medicine and public health. Despite the continuous information accumulation of clinically significant DDIs, there are few open-access knowledge systems dedicated to the curation of DDI associations. To facilitate the clinicians to screen for dangerous drug combinations and improve health systems, we present DDInter, a curated DDI database with comprehensive data, practical medication guidance, intuitive function interface, and powerful visualization to the scientific community. Currently, DDInter contains about 0.24M DDI associations connecting 1833 approved drugs (1972 entities). Each drug is annotated with basic chemical and pharmacological information and its interaction network. For DDI associations, abundant and professional annotations are provided, including severity, mechanism description, strategies for managing potential side effects, alternative medications, etc. The drug entities and interaction entities are efficiently cross-linked. In addition to basic query and browsing, the prescription checking function is developed to facilitate clinicians to decide whether drugs combinations can be used safely. It can also be used for informatics-based DDI investigation and evaluation of other prediction frameworks. We hope that DDInter will prove useful in improving clinical decision-making and patient safety. DDInter is freely available, without registration, at http://ddinter.scbdd.com/.
Assuntos
Bases de Dados Factuais , Interações Medicamentosas/genética , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/classificação , Software , Tomada de Decisão Clínica , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/genética , Humanos , Segurança do PacienteRESUMO
In drug discovery, selecting targeted molecules is crucial as the target could directly affect drug efficacy and the treatment outcomes. As a member of the CCN family, CTGF (also known as CCN2) is an essential regulator in the progression of various diseases, including fibrosis, cancer, neurological disorders, and eye diseases. Understanding the regulatory mechanisms of CTGF in different diseases may contribute to the discovery of novel drug candidates. Summarizing the CTGF-targeting and -inhibitory drugs is also beneficial for the analysis of the efficacy, applications, and limitations of these drugs in different disease models. Therefore, we reviewed the CTGF structure, the regulatory mechanisms in various diseases, and drug development in order to provide more references for future drug discovery.
Assuntos
Fator de Crescimento do Tecido Conjuntivo , Descoberta de Drogas , Humanos , Fator de Crescimento do Tecido Conjuntivo/metabolismo , Descoberta de Drogas/métodos , Animais , Neoplasias/tratamento farmacológico , Neoplasias/metabolismo , Oftalmopatias/tratamento farmacológico , Oftalmopatias/metabolismo , Fibrose , Doenças do Sistema Nervoso/tratamento farmacológico , Doenças do Sistema Nervoso/metabolismo , Regulação da Expressão Gênica/efeitos dos fármacosRESUMO
BACKGROUND: Allele-specific binding (ASB) events occur when transcription factors (TFs) bind more favorably to one of the two parental alleles at heterozygous single nucleotide polymorphisms (SNPs). Evidence suggests that ASB events could reveal the impact of sequence variations on TF binding and may have implications for the risk of diseases. RESULTS: Here we present ASB-analyzer, a software platform that enables the users to quickly and efficiently input raw sequencing data to generate individual reports containing the cytogenetic map of ASB SNPs and their associated phenotypes. This interactive tool thereby combines ASB SNP identification, biological annotation, motif analysis, phenotype associations and report summary in one pipeline. With this pipeline, we identified 3772 ASB SNPs from thirty GM12878 ChIP-seq datasets and demonstrated that the ASB SNPs were more likely to be enriched at important sites in TF-binding domains. CONCLUSIONS: ASB-analyzer is a user-friendly tool that enables the detection, characterization and visualization of ASB SNPs. It is implemented in Python, R and bash shell and packaged in the Conda environment. It is available as an open-source tool on GitHub at https://github.com/Liying1996/ASBanalyzer .
Assuntos
Polimorfismo de Nucleotídeo Único , Fatores de Transcrição , Alelos , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo , Software , Ligação Proteica , Sítios de LigaçãoRESUMO
Methotrexate (MTX) is the first-line treatment for rheumatoid arthritis (RA). However, after long-term treatment, some patients develop resistance. P-glycoprotein (P-gp), as an indispensable drug transporter, is essential for mediating this MTX resistance. In addition, nobiletin (NOB), a naturally occurring polymethoxylated flavonoid, has also been shown to reverse P-gp-mediated MTX resistance in RA groups; however, the precise role of NOB in this process is still unclear. Here, we administered MTX and NOB alone or in combination to collagen II-induced arthritic (CIA) mice and evaluated disease severity using the arthritis index, synovial histopathological changes, immunohistochemistry, and P-gp expression. In addition, we used conventional RNA-seq to identify targets and possible pathways through which NOB reverses MTX-induced drug resistance. We found that NOB in combination with MTX could enhance its performance in synovial tissue and decrease P-gp expression in CIA mice compared to MTX treatment alone. In vitro, in MTX-resistant fibroblast-like synoviocytes from CIA cells (CIA-FLS/MTX), we show that NOB treatment downregulated the PI3K/AKT/HIF-1α pathway, thereby reducing the synthesis of the P-gp protein. In addition, NOB significantly inhibited glycolysis and metabolic activity of CIA-FLS/MTX cells, which could reduce the production of ATP and block P-gp, ultimately decreasing the efflux of MTX and maintaining its anti-RA effects. In conclusion, this study shows that NOB overcomes MTX resistance in CIA-FLS/MTX cells through the PI3K/AKT/HIF-1α pathway, simultaneously influencing metabolic processes and inhibiting P-gp-induced drug efflux.
Assuntos
Artrite Experimental , Artrite Reumatoide , Resistência a Medicamentos , Flavonas , Biossíntese de Proteínas , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/genética , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/metabolismo , Animais , Artrite Experimental/tratamento farmacológico , Artrite Experimental/patologia , Artrite Reumatoide/tratamento farmacológico , Artrite Reumatoide/metabolismo , Resistência a Medicamentos/efeitos dos fármacos , Fibroblastos/metabolismo , Flavonas/farmacologia , Flavonas/uso terapêutico , Expressão Gênica/efeitos dos fármacos , Humanos , Metotrexato/farmacologia , Camundongos , Fosfatidilinositol 3-Quinases/genética , Fosfatidilinositol 3-Quinases/metabolismo , Biossíntese de Proteínas/efeitos dos fármacos , Inibidores da Síntese de Proteínas/farmacologia , Inibidores da Síntese de Proteínas/uso terapêutico , Proteínas Proto-Oncogênicas c-akt/genética , Proteínas Proto-Oncogênicas c-akt/metabolismoRESUMO
The chemotherapy of triple-negative breast cancer based on doxorubicin (DOX) regimens suffers from great challenges on toxicity and autophagy raised off-target. In this study, a conjugate methotrexate-polyethylene glycol (shorten as MTX-PEG)-modified CG/DMMA polymeric micelles were prepared to endue DOX tumor selectivity and synergistic autophagic flux interference to reduce systematic toxicity and to improve anti-tumor capacity. The micelles could effectively promote the accumulation of autophagosomes in tumor cells and interfere with the degradation process of autophagic flux, collectively inducing autophagic death of tumor cells. In vivo and in vitro experiments showed that the micelles could exert improved anti-tumor effect and specificity, as well as reduced accumulation and damage of chemotherapeutic drugs in normal organs. The potential mechanism of synergistic autophagic death exerted by the synthesized micelles in MDA-MB-231 cells has been performed by autophagic flux-related pathway.
Assuntos
Neoplasias da Mama , Neoplasias de Mama Triplo Negativas , Humanos , Feminino , Micelas , Metotrexato , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Neoplasias da Mama/tratamento farmacológico , Linhagem Celular Tumoral , Doxorrubicina , PolímerosRESUMO
Overexpressed matrix metalloproteinases, hypoxia microenvironment, and metabolic abnormality are important pathological signs of rheumatoid arthritis (RA). Designing a delivery carrier according to the pathological characteristics of RA that can control drug release in response to disease severity may be a promising treatment strategy. Psoralen is the main active ingredient isolated from Psoralea corylifolia L. and possesses excellent anti-inflammatory activities as well as improving bone homeostasis. However, the specific underlying mechanisms, particularly the possible relationships between the anti-RA effects of psoralen and related metabolic network, remain largely unexplored. Furthermore, psoralen shows systemic side effects and has unsatisfactory solubility. Therefore, it is desirable to develop a novel delivery system to maximize psoralen's therapeutic effect. In this study, a self-assembled degradable hydrogel platform is developed that delivers psoralen and calcium peroxide to arthritic joints and controls the release of psoralen and oxygen according to inflammatory stimulation, to regulate homeostasis and the metabolic disorder of the anoxic arthritic microenvironment. Therefore, the hydrogel drug delivery system based on the responsiveness of the inflammatory microenvironment and regulation of metabolism provides a new therapeutic strategy for RA treatment.
Assuntos
Artrite Reumatoide , Ficusina , Humanos , Ficusina/farmacologia , Hidrogéis , Extratos Vegetais , Osso e OssosRESUMO
Scoring functions (SFs) based on complex machine learning (ML) algorithms have gradually emerged as a promising alternative to overcome the weaknesses of classical SFs. However, extensive efforts have been devoted to the development of SFs based on new protein-ligand interaction representations and advanced alternative ML algorithms instead of the energy components obtained by the decomposition of existing SFs. Here, we propose a new method named energy auxiliary terms learning (EATL), in which the scoring components are extracted and used as the input for the development of three levels of ML SFs including EATL SFs, docking-EATL SFs and comprehensive SFs with ascending VS performance. The EATL approach not only outperforms classical SFs for the absolute performance (ROC) and initial enrichment (BEDROC) but also yields comparable performance compared with other advanced ML-based methods on the diverse subset of Directory of Useful Decoys: Enhanced (DUD-E). The test on the relatively unbiased actives as decoys (AD) dataset also proved the effectiveness of EATL. Furthermore, the idea of learning from SF components to yield improved screening power can also be extended to other docking programs and SFs available.
Assuntos
Descoberta de Drogas , Aprendizado de Máquina , Simulação de Acoplamento Molecular , Proteínas/química , Ligação ProteicaRESUMO
BACKGROUND: With the increasing development of biotechnology and information technology, publicly available data in chemistry and biology are undergoing explosive growth. Such wealthy information in these resources needs to be extracted and then transformed to useful knowledge by various data mining methods. However, a main computational challenge is how to effectively represent or encode molecular objects under investigation such as chemicals, proteins, DNAs and even complicated interactions when data mining methods are employed. To further explore these complicated data, an integrated toolkit to represent different types of molecular objects and support various data mining algorithms is urgently needed. RESULTS: We developed a freely available R/CRAN package, called BioMedR, for molecular representations of chemicals, proteins, DNAs and pairwise samples of their interactions. The current version of BioMedR could calculate 293 molecular descriptors and 13 kinds of molecular fingerprints for small molecules, 9920 protein descriptors based on protein sequences and six types of generalized scale-based descriptors for proteochemometric modeling, more than 6000 DNA descriptors from nucleotide sequences and six types of interaction descriptors using three different combining strategies. Moreover, this package realized five similarity calculation methods and four powerful clustering algorithms as well as several useful auxiliary tools, which aims at building an integrated analysis pipeline for data acquisition, data checking, descriptor calculation and data modeling. CONCLUSION: BioMedR provides a comprehensive and uniform R package to link up different representations of molecular objects with each other and will benefit cheminformatics/bioinformatics and other biomedical users. It is available at: https://CRAN.R-project.org/package=BioMedR and https://github.com/wind22zhu/BioMedR/.
Assuntos
Biologia Computacional/métodos , Sistemas de Gerenciamento de Base de Dados , Gerenciamento de Dados/métodos , Bases de Dados de Compostos Químicos , Bases de Dados Genéticas , HumanosRESUMO
Computational methods have become indispensable tools to accelerate the drug discovery process and alleviate the excessive dependence on time-consuming and labor-intensive experiments. Traditional feature-engineering approaches heavily rely on expert knowledge to devise useful features, which could be costly and sometimes biased. The emerging deep learning (DL) methods deliver a data-driven method to automatically learn expressive representations from complex raw data. Inspired by this, researchers have attempted to apply various deep neural network models to simplified molecular input line entry specification (SMILES) strings, which contain all the composition and structure information of molecules. However, current models usually suffer from the scarcity of labeled data. This results in a low generalization ability of SMILES-based DL models, which prevents them from competing with the state-of-the-art computational methods. In this study, we utilized the BiLSTM (bidirectional long short term merory) attention network (BAN) in which we employed a novel multi-step attention mechanism to facilitate the extracting of key features from the SMILES strings. Meanwhile, SMILES enumeration was utilized as a data augmentation method in the training phase to substantially increase the number of labeled data and enlarge the probability of mining more patterns from complex SMILES. We again took advantage of SMILES enumeration in the prediction phase to rectify model prediction bias and provide a more accurate prediction. Combined with the BAN model, our strategies can greatly improve the performance of latent features learned from SMILES strings. In 11 canonical absorption, distribution, metabolism, excretion and toxicity-related tasks, our method outperformed the state-of-the-art approaches.
Assuntos
Quimioinformática/métodos , Aprendizado Profundo , Descoberta de Drogas/métodos , Software , Algoritmos , Desenvolvimento de Medicamentos , Projetos de PesquisaRESUMO
BACKGROUND: High-throughput screening (HTS) and virtual screening (VS) have been widely used to identify potential hits from large chemical libraries. However, the frequent occurrence of 'noisy compounds' in the screened libraries, such as compounds with poor drug-likeness, poor selectivity or potential toxicity, has greatly weakened the enrichment capability of HTS and VS campaigns. Therefore, the development of comprehensive and credible tools to detect noisy compounds from chemical libraries is urgently needed in early stages of drug discovery. RESULTS: In this study, we developed a freely available integrated python library for negative design, called Scopy, which supports the functions of data preparation, calculation of descriptors, scaffolds and screening filters, and data visualization. The current version of Scopy can calculate 39 basic molecular properties, 3 comprehensive molecular evaluation scores, 2 types of molecular scaffolds, 6 types of substructure descriptors and 2 types of fingerprints. A number of important screening rules are also provided by Scopy, including 15 drug-likeness rules (13 drug-likeness rules and 2 building block rules), 8 frequent hitter rules (four assay interference substructure filters and four promiscuous compound substructure filters), and 11 toxicophore filters (five human-related toxicity substructure filters, three environment-related toxicity substructure filters and three comprehensive toxicity substructure filters). Moreover, this library supports four different visualization functions to help users to gain a better understanding of the screened data, including basic feature radar chart, feature-feature-related scatter diagram, functional group marker gram and cloud gram. CONCLUSION: Scopy provides a comprehensive Python package to filter out compounds with undesirable properties or substructures, which will benefit the design of high-quality chemical libraries for drug design and discovery. It is freely available at https://github.com/kotori-y/Scopy.
Assuntos
Bases de Dados de Produtos Farmacêuticos/estatística & dados numéricos , Desenho de Fármacos , Desenvolvimento de Medicamentos/métodos , Ensaios de Triagem em Larga Escala/métodos , Bibliotecas de Moléculas Pequenas , Produtos Biológicos/química , Biologia Computacional/métodos , Descoberta de Drogas/métodos , Estabilidade de Medicamentos , Humanos , Estrutura Molecular , Preparações Farmacêuticas/química , Reprodutibilidade dos Testes , Projetos de PesquisaRESUMO
BACKGROUND: Substructure screening is widely applied to evaluate the molecular potency and ADMET properties of compounds in drug discovery pipelines, and it can also be used to interpret QSAR models for the design of new compounds with desirable physicochemical and biological properties. With the continuous accumulation of more experimental data, data-driven computational systems which can derive representative substructures from large chemical libraries attract more attention. Therefore, the development of an integrated and convenient tool to generate and implement representative substructures is urgently needed. RESULTS: In this study, PySmash, a user-friendly and powerful tool to generate different types of representative substructures, was developed. The current version of PySmash provides both a Python package and an individual executable program, which achieves ease of operation and pipeline integration. Three types of substructure generation algorithms, including circular, path-based and functional group-based algorithms, are provided. Users can conveniently customize their own requirements for substructure size, accuracy and coverage, statistical significance and parallel computation during execution. Besides, PySmash provides the function for external data screening. CONCLUSION: PySmash, a user-friendly and integrated tool for the automatic generation and implementation of representative substructures, is presented. Three screening examples, including toxicophore derivation, privileged motif detection and the integration of substructures with machine learning (ML) models, are provided to illustrate the utility of PySmash in safety profile evaluation, therapeutic activity exploration and molecular optimization, respectively. Its executable program and Python package are available at https://github.com/kotori-y/pySmash.
Assuntos
Biologia Computacional/métodos , Descoberta de Drogas/métodos , Aprendizado de Máquina , Software , Testes de Carcinogenicidade/métodos , Carcinógenos , Ensaios de Seleção de Medicamentos Antitumorais/métodos , HumanosRESUMO
Matched molecular pairs analysis (MMPA) has become a powerful tool for automatically and systematically identifying medicinal chemistry transformations from compound/property datasets. However, accurate determination of matched molecular pair (MMP) transformations largely depend on the size and quality of existing experimental data. Lack of high-quality experimental data heavily hampers the extraction of more effective medicinal chemistry knowledge. Here, we developed a new strategy called quantitative structure-activity relationship (QSAR)-assisted-MMPA to expand the number of chemical transformations and took the logD7.4 property endpoint as an example to demonstrate the reliability of the new method. A reliable logD7.4 consensus prediction model was firstly established, and its applicability domain was strictly assessed. By applying the reliable logD7.4 prediction model to screen two chemical databases, we obtained more high-quality logD7.4 data by defining a strict applicability domain threshold. Then, MMPA was performed on the predicted data and experimental data to derive more chemical rules. To validate the reliability of the chemical rules, we compared the magnitude and directionality of the property changes of the predicted rules with those of the measured rules. Then, we compared the novel chemical rules generated by our proposed approach with the published chemical rules, and found that the magnitude and directionality of the property changes were consistent, indicating that the proposed QSAR-assisted-MMPA approach has the potential to enrich the collection of rule types or even identify completely novel rules. Finally, we found that the number of the MMP rules derived from the experimental data could be amplified by the predicted data, which is helpful for us to analyze the medicinal chemical rules in local chemical environment. In summary, the proposed QSAR-assisted-MMPA approach could be regarded as a very promising strategy to expand the chemical transformation space for lead optimization, especially when no enough experimental data can support MMPA.