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1.
Int J Mol Sci ; 22(15)2021 Jul 28.
Artigo em Inglês | MEDLINE | ID: mdl-34360838

RESUMO

Drug-induced liver toxicity is one of the significant safety challenges for the patient's health and the pharmaceutical industry. It causes termination of drug candidates in clinical trials and also the retractions of approved drugs from the market. Thus, it is essential to identify hepatotoxic compounds in the initial stages of drug development process. The purpose of this study is to construct quantitative structure activity relationship models using machine learning algorithms and systematical feature selection methods for molecular descriptor sets. The models were built from a large and diverse set of 1253 drug compounds and were validated internally with 10-fold cross-validation. In this study, we applied a variety of feature selection techniques to extract the optimal subset of descriptors as modeling features to improve the prediction performance. Experimental results suggested that the support vector machine-based classifier had achieved a better classification accuracy with reduced molecular descriptors. The final optimal model provides an accuracy of 0.811, a sensitivity of 0.840, a specificity of 0.783 and Mathew's correlation coefficient of 0.623 with an internal validation set. Furthermore, this model outperformed the prior studies while evaluated in both the internal and external test sets. The utilization of distinct optimal molecular descriptors as modeling features produce an in silico model with a superior performance.


Assuntos
Doença Hepática Induzida por Substâncias e Drogas , Simulação por Computador , Fígado/efeitos dos fármacos , Modelos Biológicos , Relação Quantitativa Estrutura-Atividade , Máquina de Vetores de Suporte , Confiabilidade dos Dados , Humanos , Sensibilidade e Especificidade
2.
Int J Mol Sci ; 22(15)2021 Jul 29.
Artigo em Inglês | MEDLINE | ID: mdl-34360886

RESUMO

Xanthine oxidase (XO) is an important target for the effective treatment of hyperuricemia-associated diseases. A series of novel 2-substituted 6-oxo-1,6-dihydropyrimidine-5-carboxylic acids (ODCs) as XO inhibitors (XOIs) with remarkable activities have been reported recently. To better understand the key pharmacological characteristics of these XOIs and explore more hit compounds, in the present study, the three-dimensional quantitative structure-activity relationship (3D-QSAR), molecular docking, pharmacophore modeling, and molecular dynamics (MD) studies were performed on 46 ODCs. The constructed 3D-QSAR models exhibited reliable predictability with satisfactory validation parameters, including q2 = 0.897, R2 = 0.983, rpred2 = 0.948 in a CoMFA model, and q2 = 0.922, R2 = 0.990, rpred2 = 0.840 in a CoMSIA model. Docking and MD simulations further gave insights into the binding modes of these ODCs with the XO protein. The results indicated that key residues Glu802, Arg880, Asn768, Thr1010, Phe914, and Phe1009 could interact with ODCs by hydrogen bonds, π-π stackings, or hydrophobic interactions, which might be significant for the activity of these XOIs. Four potential hits were virtually screened out using the constructed pharmacophore model in combination with molecular dockings and ADME predictions. The four hits were also found to be relatively stable in the binding pocket by MD simulations. The results in this study might provide effective information for the design and development of novel XOIs.


Assuntos
Ácidos Carboxílicos/química , Inibidores Enzimáticos/química , Simulação de Acoplamento Molecular/métodos , Simulação de Dinâmica Molecular , Xantina Oxidase/antagonistas & inibidores , Xantina Oxidase/química , Desenho de Fármacos , Inibidores Enzimáticos/uso terapêutico , Humanos , Ligação de Hidrogênio , Interações Hidrofóbicas e Hidrofílicas , Hiperuricemia/tratamento farmacológico , Estrutura Molecular , Ligação Proteica , Relação Quantitativa Estrutura-Atividade
3.
J Agric Food Chem ; 69(33): 9520-9528, 2021 Aug 25.
Artigo em Inglês | MEDLINE | ID: mdl-34382783

RESUMO

Gray mold, caused by Botrytis cinerea, is one of the most destructive fungal diseases in crops, responsible for significant economic losses. In search of natural product-based fungicides, we designed and synthesized a series of novel 3,4-dichlorophenyl isoxazole-substituted stilbene derivatives, and their in vivo antifungal activities against B. cinerea were evaluated. The results indicated that some of the target molecules demonstrated remarkable efficiency for the control of tomato gray mold. In particular, compound 5r displayed the highest fungicidal potency with an inhibition rate of 56.11% comparable to that of positive control boscalid (66.96%). Moreover, a hologram quantitative structure-activity relationship (HQSAR) model with good predictive capability was developed to provide in-depth insight into the activity profiles of these compounds. Preliminary mechanism studies suggested that compound 5r might exert its antifungal effect by changing hyphal morphology and increasing the membrane permeability. The present study contributes to the development of natural stilbene derivatives as alternative bioactive agents against B. cinerea.


Assuntos
Fungicidas Industriais , Estilbenos , Botrytis , Fungicidas Industriais/farmacologia , Isoxazóis , Doenças das Plantas , Relação Quantitativa Estrutura-Atividade , Estilbenos/farmacologia
4.
J Agric Food Chem ; 69(33): 9557-9570, 2021 Aug 25.
Artigo em Inglês | MEDLINE | ID: mdl-34382800

RESUMO

Succinate dehydrogenase inhibitors (SDHIs) have emerged in fungicide markets as one of the fastest-growing categories that are widely applied in agricultural production for crop protection. Currently, the structural modification focusing on the flexible amide link of SDHI molecules is being gradually identified as one of the innovative strategies for developing novel highly efficient and broad-spectrum fungicides. Based on the above structural features, a series of pyrazole-4-acetohydrazide derivatives potentially targeting fungal SDH were constructed and evaluated for their antifungal effects against Rhizoctonia solani, Fusarium graminearum, and Botrytis cinerea. Strikingly, the in vitro EC50 values of constructed pyrazole-4-acetohydrazides 6w against R. solani, 6c against F. graminearum, and 6f against B. cinerea were, respectively, determined as 0.27, 1.94, and 1.93 µg/mL, which were obviously superior to that of boscalid against R. solani (0.94 µg/mL), fluopyram against F. graminearum (9.37 µg/mL), and B. cinerea (1.94 µg/mL). Concurrently, the effects of the substituent steric, electrostatic, hydrophobic, and hydrogen-bond fields on structure-activity relationships were elaborated by the reliable comparative molecular field analysis and comparative molecular similarity index analysis models. Subsequently, the practical value of pyrazole-4-acetohydrazide derivative 6w as a potential SDHI was ascertained by the relative surveys on the in vivo anti-R. solani preventative efficacy, inhibitory effects against fungal SDH, and molecular docking studies. The present results provide an indispensable complement for the structural optimization of antifungal leads potentially targeting SDH.


Assuntos
Fungicidas Industriais , Succinato Desidrogenase , Botrytis , Fungicidas Industriais/farmacologia , Fusarium , Hidrazinas , Simulação de Acoplamento Molecular , Doenças das Plantas , Pirazóis/farmacologia , Relação Quantitativa Estrutura-Atividade , Rhizoctonia , Relação Estrutura-Atividade , Succinato Desidrogenase/metabolismo
5.
Int J Mol Sci ; 22(15)2021 Jul 31.
Artigo em Inglês | MEDLINE | ID: mdl-34361040

RESUMO

Pyrovalerone cathinones are potent psychoactive substances that possess a pyrrolidine moiety. Pyrovalerone-type novel psychoactive substances (NPS) are continuously detected but their pharmacology and toxicology are largely unknown. We assessed several pyrovalerone and related cathinone derivatives at the human norepinephrine (NET), dopamine (DAT), and serotonin (SERT) uptake transporters using HEK293 cells overexpressing each respective transporter. We examined the transporter-mediated monoamine efflux in preloaded cells. The receptor binding and activation potency was also assessed at the 5-HT1A, 5-HT2A, 5-HT2B, and 5-HT2C receptors. All pyrovalerone cathinones were potent DAT (IC50 = 0.02-8.7 µM) and NET inhibitors (IC50 = 0.03-4.6 µM), and exhibited no SERT activity at concentrations < 10 µM. None of the compounds induced monoamine efflux. NEH was a potent DAT/NET inhibitor (IC50 = 0.17-0.18 µM). 4F-PBP and NEH exhibited a high selectivity for the DAT (DAT/SERT ratio = 264-356). Extension of the alkyl chain enhanced NET and DAT inhibition potency, while presence of a 3,4-methylenedioxy moiety increased SERT inhibition potency. Most compounds did not exhibit any relevant activity at other monoamine receptors. In conclusion, 4F-PBP and NEH were selective DAT/NET inhibitors indicating that these substances likely produce strong psychostimulant effects and have a high abuse liability.


Assuntos
Alcaloides/química , Proteínas da Membrana Plasmática de Transporte de Dopamina/antagonistas & inibidores , Proteínas da Membrana Plasmática de Transporte de Norepinefrina/antagonistas & inibidores , Psicotrópicos/química , Pirrolidinas/química , Proteínas da Membrana Plasmática de Transporte de Serotonina/metabolismo , Alcaloides/farmacologia , Monoaminas Biogênicas/metabolismo , Proteínas da Membrana Plasmática de Transporte de Dopamina/metabolismo , Células HEK293 , Humanos , Proteínas da Membrana Plasmática de Transporte de Norepinefrina/metabolismo , Ligação Proteica , Psicotrópicos/farmacologia , Pirrolidinas/farmacologia , Relação Quantitativa Estrutura-Atividade , Inibidores de Captação de Serotonina/química , Inibidores de Captação de Serotonina/farmacologia
6.
Int J Mol Sci ; 22(15)2021 Aug 03.
Artigo em Inglês | MEDLINE | ID: mdl-34361118

RESUMO

Thrombosis is a life-threatening disease with a high mortality rate in many countries. Even though anti-thrombotic drugs are available, their serious side effects compel the search for safer drugs. In search of a safer anti-thrombotic drug, Quantitative Structure-Activity Relationship (QSAR) could be useful to identify crucial pharmacophoric features. The present work is based on a larger data set comprising 1121 diverse compounds to develop a QSAR model having a balance of acceptable predictive ability (Predictive QSAR) and mechanistic interpretation (Mechanistic QSAR). The developed six parametric model fulfils the recommended values for internal and external validation along with Y-randomization parameters such as R2tr = 0.831, Q2LMO = 0.828, R2ex = 0.783. The present analysis reveals that anti-thrombotic activity is found to be correlated with concealed structural traits such as positively charged ring carbon atoms, specific combination of aromatic Nitrogen and sp2-hybridized carbon atoms, etc. Thus, the model captured reported as well as novel pharmacophoric features. The results of QSAR analysis are further vindicated by reported crystal structures of compounds with factor Xa. The analysis led to the identification of useful novel pharmacophoric features, which could be used for future optimization of lead compounds.


Assuntos
Fibrinolíticos/farmacologia , Compostos Heterocíclicos/farmacologia , Trombose/tratamento farmacológico , Fibrinolíticos/química , Compostos Heterocíclicos/química , Humanos , Modelos Moleculares , Relação Quantitativa Estrutura-Atividade
7.
Comput Methods Programs Biomed ; 209: 106347, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34399152

RESUMO

BACKGROUND AND OBJECTIVES: Overexpression of prosurvival Bcl-2 family members make tumor cells resistant to conventional cancer therapeutic agents. It is commonly observed feature in many different types of human tumors. Hence, small-molecules as Bcl-2 inhibitors may have a promising therapeutic potential for the treatment of human cancer. The given study focusses on development of novel and small Bcl-2 inhibitors using ligand-based drug design approach. METHODS: Ligand based pharmacophore was generated using the PHASE tool of Schrödinger and screened ZINC database through ZINCPharmer webserver to identify compounds with similar features. Compounds having good fitness score were selected for molecular docking and binding interactions were compared with drugs in market as well as trials. QSAR model was generated using advanced AutoQSAR tool and validated for prediction of unknown compounds. QSAR prediction of in silico active identified three potential compounds and were subjected to investigate stability by molecular dynamics simulations and MM-PBSA binding energy calculations. RESULTS: Study identified three in silico potential molecules with good stability and binding affinity. Further substructure search and pIC50 value prediction has identified six more molecules. Total nine molecules have demonstrated good drug likeness features. CONCLUSION: Final oral rat LD50 calculation of nine molecules has identified three hit molecules i.e., ZINC76760927, ZINC76768675 and ZINC52767796 for further in vitro and in vivo testing as safe and potential Bcl-2 inhibitors.


Assuntos
Neoplasias , Relação Quantitativa Estrutura-Atividade , Animais , Ligantes , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Neoplasias/tratamento farmacológico , Ratos
8.
SAR QSAR Environ Res ; 32(9): 689-698, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34293992

RESUMO

Perhaps there is some similarity between the coronavirus of 2017 and the COVID-19. Consequently, a predictive model for the antiviral activity for the Middle East respiratory syndrome coronavirus (MERS-CoV, 2017) could be useful for designing the strategy and tactics in the struggle with coronaviruses in general and with COVID 19 in particular. Quantitative structure-activity relationships (QSARs) of inhibitory activity to MERS-CoV were developed. The index of ideality of correlation was applied to build up these models for the antiviral activity. The statistical quality of the best model is quite good (r2 = 0.84). A mechanistic interpretation of these models based on the molecular features with strong positive (i.e. promoters for endpoint increase) and strong negative (i.e. promoters for endpoint decrease) influence on the inhibitory activity is suggested. A collection of possible biologically active compounds, constructed using data on the above molecular features which are statistically reliable promoters of increase or decrease of the activity, is presented.


Assuntos
Antivirais/farmacologia , COVID-19/tratamento farmacológico , Método de Monte Carlo , Relação Quantitativa Estrutura-Atividade , SARS-CoV-2/efeitos dos fármacos , Humanos
9.
J Mol Graph Model ; 108: 107968, 2021 11.
Artigo em Inglês | MEDLINE | ID: mdl-34311260

RESUMO

NF-κB is a central regulator of immunity and inflammation. It is suggested that the inflammatory response mediated by SARS-CoV-2 is predominated by NF-κB activation. Thus, NF-κB inhibition is considered a potential therapeutic strategy for COVID-19. The aim of this study was to identify potential anti-inflammation lead molecules that target NF-κB using a quantitative structure-activity relationships (QSAR) model of currently used and investigated anti-inflammatory drugs as the basis for screening. We applied an integrated approach by starting with the inflammation-based QSAR model to screen three libraries containing more than 220,000 drug-like molecules for the purpose of finding potential drugs that target the NF-κB/IκBα p50/p65 (RelA) complex. We also used QSAR models to rule out molecules that were predicted to be toxic. Among screening libraries, 382 molecules were selected as potentially nontoxic and were analyzed further by short and long molecular dynamics (MD) simulations and free energy calculations. We have discovered five hit ligands with highly predicted anti-inflammation activity and nearly no predicted toxicities which had strongly favorable protein-ligand interactions and conformational stability at the binding pocket compared to a known NF-κB inhibitor (procyanidin B2). We propose these hit molecules as potential NF-κB inhibitors which can be further investigated in pre-clinical studies against SARS-CoV-2 and may be used as a scaffold for chemical optimization and drug development efforts.


Assuntos
COVID-19 , Relação Quantitativa Estrutura-Atividade , Descoberta de Drogas , Humanos , Inflamação/tratamento farmacológico , NF-kappa B/metabolismo , SARS-CoV-2
10.
Molecules ; 26(13)2021 Jul 02.
Artigo em Inglês | MEDLINE | ID: mdl-34279387

RESUMO

Tubulin has been regarded as an attractive and successful molecular target in cancer therapy and drug discovery. Vicinal diaryl is a simple scaffold found in many colchicine site tubulin inhibitors, which is also an important pharmacophoric point of tubulin binding and anti-cancer activity. As the continuation of our research work on colchicine binding site tubulin inhibitors, we designed and synthesized a series of diarylamide N-containing heterocyclic derivatives by the combination of vicinal diaryl core and N-containing heterocyclic skeletons into one hybrid though proper linkers. Among of these compounds, compound 15b containing a 5-methoxyindole group exhibited the most potent inhibitory activity against the tested three human cancer cell lines (MGC-803, PC-3 and EC-109) with IC50 values of 1.56 µM, 3.56 µM and 14.5 µM, respectively. Besides, the SARs of these compounds were preliminarily studied and summarized. The most active compound 15b produced the inhibition of tubulin polymerization in a dose-dependent manner and caused microtubule network disruption in MGC-803 cells. Therefore, compound 15b was identified as a novel tubulin polymerization inhibitor targeting the colchicine binding site. In addition, the results of molecular docking also suggested compound 15b could tightly bind into the colchicine binding site of ß-tubulin.


Assuntos
Compostos Heterocíclicos/síntese química , Moduladores de Tubulina/síntese química , Tubulina (Proteína)/química , Sítios de Ligação , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Colchicina/farmacologia , Compostos Heterocíclicos/farmacologia , Humanos , Microtúbulos/efeitos dos fármacos , Ligação Proteica , Relação Quantitativa Estrutura-Atividade , Tubulina (Proteína)/efeitos dos fármacos , Tubulina (Proteína)/metabolismo , Moduladores de Tubulina/farmacologia
11.
Molecules ; 26(13)2021 Jun 26.
Artigo em Inglês | MEDLINE | ID: mdl-34206860

RESUMO

In this paper, a combination of modification of the source and regulation of the process was used to control the degradation of PBDEs by plants and microorganisms. First, the key proteins that can degrade PBDEs in plants and microorganisms were searched in the PDB (Protein Data Bank), and a molecular docking method was used to characterize the binding ability of PBDEs to two key proteins. Next, the synergistic binding ability of PBDEs to the two key proteins was evaluated based on the queuing integral method. Based on this, three groups of three-dimensional quantitative structure-activity relationship (3D-QSAR) models of plant-microbial synergistic degradation were constructed. A total of 30 PBDE derivatives were designed using BDE-3 as the template molecule. Among them, the effect on the synergistic degradation of six PBDE derivatives, including BDE-3-4, was significantly improved (increased by more than 20%) and the environment-friendly and functional evaluation parameters were improved. Subsequently, studies on the synergistic degradation of PBDEs and their derivatives by plants and microorganisms, based on the molecular docking method, found that the addition of lipophilic groups by modification is beneficial to enhance the efficiency of synergistic degradation of PBDEs by plants and microorganisms. Further, while docking PBDEs, the number of amino acids was increased and the binding bond length was decreased compared to the template molecules, i.e., PBDE derivatives could be naturally degraded more efficiently. Finally, molecular dynamics simulation by the Taguchi orthogonal experiment and a full factorial experimental design were used to simulate the effects of various regulatory schemes on the synergistic degradation of PBDEs by plants and microorganisms. It was found that optimal regulation occurred when the appropriate amount of carbon dioxide was supplied to the plant and microbial systems. This paper aims to provide theoretical support for enhancing the synergistic degradation of PBDEs by plants and microorganisms in e-waste dismantling sites and their surrounding polluted areas, as well as, realize the research and development of green alternatives to PBDE flame retardants.


Assuntos
Retardadores de Chama/análise , Éteres Difenil Halogenados/química , Plantas/metabolismo , Poluentes do Solo/química , Solo/química , Dióxido de Carbono/química , Dióxido de Carbono/metabolismo , Bases de Dados de Proteínas , Éteres Difenil Halogenados/análise , Modelos Moleculares , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Relação Quantitativa Estrutura-Atividade , Microbiologia do Solo
12.
Molecules ; 26(13)2021 Jun 26.
Artigo em Inglês | MEDLINE | ID: mdl-34206976

RESUMO

New pyridine, pyrazoloyridine, and furopyridine derivatives substituted with naphthyl and thienyl moieties were designed and synthesized starting from 6-(naphthalen-2-yl)-2-oxo-4-(thiophen-2-yl)-1,2-dihydropyridine-3-carbonitrile (1). The chloro, methoxy, cholroacetoxy, imidazolyl, azide, and arylamino derivatives were prepared to obtain the pyridine--C2 functionalized derivatives. The derived pyrazolpyridine-N-glycosides were synthesized via heterocyclization of the C2-thioxopyridine derivative followed by glycosylation using glucose and galactose. The furopyridine derivative 14 and the tricyclic pyrido[3',2':4,5]furo[3,2-d]pyrimidine 15 were prepared via heterocyclization of the ester derivative followed by a reaction with formamide. The newly synthesized compounds were evaluated for their ability to in vitro inhibit the CDK2 enzyme. In addition, the cytotoxicity of the compounds was tested against four different human cancer cell lines (HCT-116, MCF-7, HepG2, and A549). The CDK2/cyclin A2 enzyme inhibitory results revealed that pyridone 1, 2-chloro-6-(naphthalen-2-yl)-4-(thiophen-2-yl)nicotinonitrile (4), 6-(naphthalen-2-yl)-4-(thiophen-2-yl)-1H-pyrazolo[3,4-b]pyridin-3-amine (8), S-(3-cyano-6-(naphthaen-2-yl)-4-(thiophen-2-yl)pyridin-2-yl) 2-chloroethanethioate (11), and ethyl 3-amino-6-(naphthalen-2-yl)-4-(thiophen-2-yl)furo[2,3-b]pyridine-2-carboxylate (14) are among the most active inhibitors with IC50 values of 0.57, 0.24, 0.65, 0.50, and 0.93 µM, respectively, compared to roscovitine (IC50 0.394 µM). Most compounds showed significant inhibition on different human cancer cell lines (HCT-116, MCF-7, HepG2, and A549) with IC50 ranges of 31.3-49.0, 19.3-55.5, 22.7-44.8, and 36.8-70.7 µM, respectively compared to doxorubicin (IC50 40.0, 64.8, 24.7 and 58.1 µM, respectively). Furthermore, a molecular docking study suggests that most of the target compounds have a similar binding mode as a reference compound in the active site of the CDK2 enzyme. The structural requirements controlling the CDK2 inhibitory activity were determined through the generation of a statistically significant 2D-QSAR model.


Assuntos
Antineoplásicos/farmacologia , Quinase 2 Dependente de Ciclina/antagonistas & inibidores , Ensaios de Seleção de Medicamentos Antitumorais/métodos , Inibidores de Proteínas Quinases/farmacologia , Pirazóis/farmacologia , Piridinas/química , Antineoplásicos/química , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Quinase 2 Dependente de Ciclina/química , Relação Dose-Resposta a Droga , Doxorrubicina/farmacologia , Desenho de Fármacos , Humanos , Imidazóis/química , Concentração Inibidora 50 , Simulação de Acoplamento Molecular , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/química , Pirazóis/química , Piridinas/síntese química , Piridinas/farmacologia , Pirimidinas/química , Pirimidinas/farmacologia , Relação Quantitativa Estrutura-Atividade
13.
Ecotoxicol Environ Saf ; 222: 112525, 2021 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-34274838

RESUMO

The information of the acute oral toxicity for most polycyclic aromatic hydrocarbons (PAHs) in mammals are lacking due to limited experimental resources, leading to a need to develop reliable in silico methods to evaluate the toxicity endpoint. In this study, we developed the quantitative structure-activity relationship (QSAR) models by genetic algorithm (GA) and multiple linear regression (MLR) for the rat acute oral toxicity (LD50) of PAHs following the strict validation principles of QSAR modeling recommended by OECD. The best QSAR model comprised eight simple 2D descriptors with definite physicochemical meaning, which showed that maximum atom-type electrotopological state, van der Waals surface area, mean atomic van der Waals volume, and total number of bonds are main influencing factors for the toxicity endpoint. A true external set (554 compounds) without rat acute oral toxicity values, and 22 limit test compounds, were firstly predicted along with reliability assessment. We also compared our proposed model with the OPERA predictions and recently published literature to prove the prediction reliability. Furthermore, the interspecies toxicity (iST) models of PAHs between rat and mouse were also established, validated and employed for filling data gap. Overall, our developed models should be applicable to new or untested or not yet synthesized PAHs falling within the applicability domain (AD) of the models for rapid acute oral toxicity prediction, thus being important for environmental or personal exposure risk assessment under regulatory frameworks.


Assuntos
Hidrocarbonetos Policíclicos Aromáticos , Relação Quantitativa Estrutura-Atividade , Animais , Dose Letal Mediana , Modelos Lineares , Camundongos , Hidrocarbonetos Policíclicos Aromáticos/toxicidade , Ratos , Reprodutibilidade dos Testes
14.
Int J Mol Sci ; 22(13)2021 Jun 22.
Artigo em Inglês | MEDLINE | ID: mdl-34206613

RESUMO

Many chemicals that enter the environment, food chain, and the human body can disrupt androgen-dependent pathways and mimic hormones and therefore, may be responsible for multiple diseases from reproductive to tumor. Thus, modeling and predicting androgen receptor activity is an important area of research. The aim of the current study was to find a method or combination of methods to predict compounds that can bind to and/or disrupt the androgen receptor, and thereby guide decision making and further analysis. A stepwise procedure proceeded from analysis of protein structures from human, chimp, and rat, followed by docking and subsequent ligand, and statistics based techniques that improved classification gradually. The best methods used multivariate logistic regression of combinations of chimpanzee protein structural docking scores, extended connectivity fingerprints, and naïve Bayesians of known binders and non-binders. Combination or consensus methods included data from a variety of procedures to improve the final model accuracy.


Assuntos
Teorema de Bayes , Disruptores Endócrinos/química , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Receptores Androgênicos/química , Disruptores Endócrinos/metabolismo , Humanos , Ligantes , Modelos Logísticos , Estrutura Molecular , Ligação Proteica , Relação Quantitativa Estrutura-Atividade , Curva ROC , Receptores Androgênicos/metabolismo , Reprodutibilidade dos Testes
15.
J Chem Inf Model ; 61(7): 3240-3254, 2021 07 26.
Artigo em Inglês | MEDLINE | ID: mdl-34197105

RESUMO

De novo molecule design through the molecular generative model has gained increasing attention in recent years. Here, a novel generative model was proposed by integrating the three-dimensional (3D) structural information of the protein binding pocket into the conditional RNN (cRNN) model to control the generation of drug-like molecules. In this model, the composition of the protein binding pocket is effectively characterized through a coarse-grain strategy and the 3D information of the pocket can be represented by the sorted eigenvalues of the Coulomb matrix (EGCM) of the coarse-grained atoms composing the binding pocket. In current work, we used our EGCM method and a previously reported binding pocket descriptor, DeeplyTough, to train cRNN models and evaluated their performance. It has been shown that the model trained with the constraint of protein environment information has a clear tendency on generating compounds with higher similarity to the original X-ray-bound ligand than the normal RNN model and also better docking scores. Our results demonstrate the potential application of the controlled generative model for the targeted molecule generation and guided exploration on the drug-like chemical space.


Assuntos
Proteínas , Relação Quantitativa Estrutura-Atividade , Sítios de Ligação , Modelos Moleculares , Ligação Proteica , Proteínas/metabolismo
16.
Int J Mol Sci ; 22(14)2021 Jul 06.
Artigo em Inglês | MEDLINE | ID: mdl-34298898

RESUMO

The aim was to study the inhibitory effects of coumarin derivatives on the plant pathogenic fungi, as well as beneficial bacteria and nematodes. The antifungal assay was performed on four cultures of phytopathogenic fungi by measuring the radial growth of the fungal colonies. Antibacterial activity was determined by the broth microdilution method performed on two beneficial soil organisms. Nematicidal activity was tested on two entomopathogenic nematodes. The quantitative structure-activity relationship (QSAR) model was generated by genetic algorithm, and toxicity was estimated by T.E.S.T. software. The mode of inhibition of enzymes related to the antifungal activity is elucidated by molecular docking. Coumarin derivatives were most effective against Macrophomina phaseolina and Sclerotinia sclerotiorum, but were not harmful against beneficial nematodes and bacteria. A predictive QSAR model was obtained for the activity against M. phaseolina (R2tr = 0.78; R2ext = 0.67; Q2loo = 0.67). A QSAR study showed that multiple electron-withdrawal groups, especially at position C-3, enhanced activities against M. phaseolina, while the hydrophobic benzoyl group at the pyrone ring, and -Br, -OH, -OCH3, at the benzene ring, may increase inhibition of S. sclerotiourum. Tested compounds possibly act inhibitory against plant wall-degrading enzymes, proteinase K. Coumarin derivatives are the potentially active ingredient of environmentally friendly plant-protection products.


Assuntos
Antibacterianos/farmacologia , Antifúngicos/farmacologia , Cumarínicos/farmacologia , Plantas/microbiologia , Ascomicetos/efeitos dos fármacos , Testes de Sensibilidade Microbiana/métodos , Simulação de Acoplamento Molecular/métodos , Relação Quantitativa Estrutura-Atividade
17.
Environ Sci Technol ; 55(14): 9958-9967, 2021 07 20.
Artigo em Inglês | MEDLINE | ID: mdl-34240848

RESUMO

Deep learning (DL) offers an unprecedented opportunity to revolutionize the landscape of toxicity prediction based on quantitative structure-activity relationship (QSAR) studies in the big data era. However, the structural description in the reported DL-QSAR models is still restricted to the two-dimensional level. Inspired by point clouds, a type of geometric data structure, a novel three-dimensional (3D) molecular surface point cloud with electrostatic potential (SepPC) was proposed to describe chemical structures. Each surface point of a chemical is assigned its 3D coordinate and molecular electrostatic potential. A novel DL architecture SepPCNET was then introduced to directly consume unordered SepPC data for toxicity classification. The SepPCNET model was trained on 1317 chemicals tested in a battery of 18 estrogen receptor-related assays of the ToxCast program. The obtained model recognized the active and inactive chemicals at accuracies of 82.8 and 88.9%, respectively, with a total accuracy of 88.3% on the internal test set and 92.5% on the external test set, which outperformed other up-to-date machine learning models and succeeded in recognizing the difference in the activity of isomers. Additional insights into the toxicity mechanism were also gained by visualizing critical points and extracting data-driven point features of active chemicals.


Assuntos
Estrogênios , Relação Quantitativa Estrutura-Atividade , Estrogênios/toxicidade , Humanos , Eletricidade Estática
18.
Int J Mol Sci ; 22(11)2021 Jun 06.
Artigo em Inglês | MEDLINE | ID: mdl-34204026

RESUMO

This work aimed to construct 3D-QSAR CoMFA and CoMSIA models for a series of 31 FAAH inhibitors, containing the 1,3,4-oxadiazol-2-one moiety. The obtained models were characterized by good statistical parameters: CoMFA Q2 = 0.61, R2 = 0.98; CoMSIA Q2 = 0.64, R2 = 0.93. The CoMFA model field contributions were 54.1% and 45.9% for steric and electrostatic fields, respectively. In the CoMSIA model, electrostatic, steric, hydrogen bond donor, and hydrogen acceptor properties were equal to 34.6%, 23.9%, 23.4%, and 18.0%, respectively. These models were validated by applying the leave-one-out technique, the seven-element test set (CoMFA r2test-set = 0.91; CoMSIA r2test-set = 0.91), a progressive scrambling test, and external validation criteria developed by Golbraikh and Tropsha (CoMFA r20 = 0.98, k = 0.95; CoMSIA r20 = 0.98, k = 0.89). As the statistical significance of the obtained model was confirmed, the results of the CoMFA and CoMSIA field calculation were mapped onto the enzyme binding site. It gave us the opportunity to discuss the structure-activity relationship based on the ligand-enzyme interactions. In particular, examination of the electrostatic properties of the established CoMFA model revealed fields that correspond to the regions where electropositive substituents are not desired, e.g., in the neighborhood of the 1,3,4-oxadiazol-2-one moiety. This highlights the importance of heterocycle, a highly electronegative moiety in this area of each ligand. Examination of hydrogen bond donor and acceptor properties contour maps revealed several spots where the implementation of another hydrogen-bond-donating moiety will positively impact molecules' binding affinity, e.g., in the neighborhood of the 1,3,4-oxadiazol-2-one ring. On the other hand, there is a large isopleth that refers to the favorable H-bond properties close to the terminal phenoxy group of a ligand, which means that, generally speaking, H-bond acceptors are desired in this area.


Assuntos
Simulação de Acoplamento Molecular , Oxidiazóis/química , Relação Quantitativa Estrutura-Atividade , Ligação de Hidrogênio , Concentração Inibidora 50 , Reprodutibilidade dos Testes
19.
Expert Opin Drug Metab Toxicol ; 17(8): 987-1005, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-34078212

RESUMO

Introduction: Genotoxicity is an imperative component of the human health safety assessment of chemicals. Its secure forecast is of the utmost importance for all health prevention strategies and regulations.Areas covered: We surveyed several types of alternative, animal-free approaches ((quantitative) structure-activity relationship (Q)SAR, read-across, Adverse Outcome Pathway, Integrated Approaches to Testing and Assessment) for genotoxicity prediction within the needs of regulatory frameworks, putting special emphasis on data quality and uncertainties issues.Expert opinion: (Q)SAR models and read-across approaches for in vitro bacterial mutagenicity have sufficient reliability for use in prioritization processes, and as support in regulatory decisions in combination with other types of evidence. (Q)SARs and read-across methodologies for other genotoxicity endpoints need further improvements and should be applied with caution. It appears that there is still large room for improvement of genotoxicity prediction methods. Availability of well-curated high-quality databases, covering a broader chemical space, is one of the most important needs. Integration of in silico predictions with expert knowledge, weight-of-evidence-based assessment, and mechanistic understanding of genotoxicity pathways are other key points to be addressed for the generation of more accurate and trustable results.


Assuntos
Simulação por Computador , Testes de Mutagenicidade/métodos , Mutagênicos/toxicidade , Alternativas aos Testes com Animais/métodos , Animais , Bases de Dados Factuais , Humanos , Relação Quantitativa Estrutura-Atividade , Reprodutibilidade dos Testes
20.
J Med Chem ; 64(13): 9389-9403, 2021 07 08.
Artigo em Inglês | MEDLINE | ID: mdl-34152772

RESUMO

Models intended to predict intestinal absorption are an essential part of the drug development process. Although many models exist for capturing intestinal absorption, many questions still exist around the applicability of these models to drug types like "beyond rule of 5" (bRo5) and low absorption compounds. This presents a challenge as current models have not been rigorously tested to understand intestinal absorption. Here, we assembled a large, structurally diverse dataset of ∼1000 compounds with known in vitro, preclinical, and human permeability and/or absorption data. In silico (quantitative structure-activity relationship), in vitro (Caco-2), and in vivo (rat) models were statistically evaluated for predictive performance against this human intestinal absorption dataset. We expect this evaluation to serve as a resource for DMPK scientists and medicinal/computational chemists to increase their understanding of permeability and absorption model utility and applications for academia and industry.


Assuntos
Absorção Intestinal/efeitos dos fármacos , Modelos Biológicos , Preparações Farmacêuticas/química , Relação Quantitativa Estrutura-Atividade , Animais , Células CACO-2 , Permeabilidade da Membrana Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Humanos , Estrutura Molecular , Ratos
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