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According to the WHO, antimicrobial resistance is among the top 10 threats to global health. Due to increased resistance rates, an increase in the mortality and morbidity of patients has been observed, with projections of more than 10 million deaths associated with infections caused by antibacterial resistant microorganisms. Our research group has developed a new family of pyrimido-isoquinolin-quinones showing antibacterial activities against multidrug-resistant Staphylococcus aureus. We have developed 3D-QSAR CoMFA and CoMSIA studies (r2 = 0.938; 0.895), from which 13 new derivatives were designed and synthesized. The compounds were tested in antibacterial assays against methicillin-resistant Staphylococcus aureus and other bacterial pathogens. There were 12 synthesized compounds active against Gram-positive pathogens in concentrations ranging from 2 to 32 µg/mL. The antibacterial activity of the derivatives is explained by the steric, electronic, and hydrogen-bond acceptor properties of the compounds.
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A new series of twenty-two C-5 substituted N-arylsulfonylindoles was prepared with the aim of exploring the influence of C-5 substitution on 5-HT6 receptor affinity. Eleven compounds showed moderate to high affinity at the receptor (Ki = 58-403 nM), with compound 4d being identified as the most potent ligand. However, regarding C-5 substitution, both methoxy and fluorine were detrimental for receptor affinity compared to our previously published unsubstituted compounds. In order to shed light on these observations, we performed docking and molecular dynamics simulations with the most potent compounds of each series (4d and 4l) and PUC-10, a highly active ligand previously reported by our group. The comparison brings about deeper insight about the influence of the C-5 substitution on the binding mode of the ligands, suggesting that these replacements are detrimental to the affinity due to precluding a ligand from reaching deeper inside the binding site. Additionally, CoMFA/CoMSIA studies were performed to systematize the information of the main structural and physicochemical characteristics of the ligands, which are responsible for their biological activity. The CoMFA and CoMSIA models presented high values of q2 (0.653; 0.692) and r2 (0.879; 0.970), respectively. Although the biological activity of the ligands can be explained in terms of the steric and electronic properties, it depends mainly on the electronic nature.
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Sirtuin 2 is a key enzyme in gene expression regulation that is often associated with tumor proliferation control and therefore is a relevant anticancer drug target. Anilinobenzamide derivatives have been discussed as selective sirtuin 2 inhibitors and can be developed further. In the present study, hologram and three-dimensional quantitative structure-activity relationship (HQSAR and 3D-QSAR) analyses were employed for determining structural contributions of a compound series containing human sirtuin-2-selective inhibitors that were then correlated with structural data from the literature. The final QSAR models were robust and predictive according to statistical validation (q2 and r2pred values higher than 0.85 and 0.75, respectively) and could be employed further to generate fragment contribution and contour maps. 3D-QSAR models together with information about the chemical properties of sirtuin 2 inhibitors can be useful for designing novel bioactive ligands.Communicated by Ramaswamy H. Sarma.
Assuntos
Benzamidas/farmacologia , Relação Quantitativa Estrutura-Atividade , Sirtuína 2/antagonistas & inibidores , Sirtuína 2/química , Acetilação/efeitos dos fármacos , Domínio Catalítico , Epigênese Genética/efeitos dos fármacos , Humanos , Simulação de Acoplamento Molecular , Reprodutibilidade dos Testes , Sirtuína 2/metabolismoRESUMO
BACKGROUND: A strategy for the treatment of type II diabetes mellitus is the inhibition of the enzyme known as dipeptidyl peptidase-4 (DPP-4). AIMS: This study aims to investigate the main interactions between DPP-4 and a set of inhibitors, as well as proposing potential candidates to inhibit this enzyme. METHODS: We performed molecular docking studies followed by the construction and validation of CoMFA and CoMSIA models. The information provided from these models was used to aid in the search for new candidates to inhibit DPP-4 and the design of new bioactive ligands from structural modifications in the most active molecule of the studied series. RESULTS: We were able to propose a set of analogues with biological activity predicted by the CoMFA and CoMSIA models, suggesting that our protocol can be used to guide the design of new DPP-4 inhibitors as drug candidates to treat diabetes. CONCLUSION: Once the integration of the techniques mentioned in this article was effective, our strategy can be applied to design possible new DPP-4 inhibitors as candidates to treat diabetes.
Assuntos
Diabetes Mellitus Tipo 2/tratamento farmacológico , Dipeptidil Peptidase 4/metabolismo , Inibidores da Dipeptidil Peptidase IV/farmacologia , Desenho de Fármacos , Hipoglicemiantes/farmacologia , Diabetes Mellitus Tipo 2/metabolismo , Inibidores da Dipeptidil Peptidase IV/síntese química , Inibidores da Dipeptidil Peptidase IV/química , Humanos , Hipoglicemiantes/síntese química , Hipoglicemiantes/química , Simulação de Acoplamento Molecular , Estrutura MolecularRESUMO
Fatty Acid Amide Hydrolase (FAAH) is one of the main enzymes responsible for endocannabinoid metabolism. Inhibition of FAAH increases endogenous levels of fatty acid ethanolamides such as anandamide (AEA) and thus consitutes an indirect strategy that can be used to modulate endocannabinoid tone. In the present work, we present a three-dimensional quantitative structure-activity relationships/comparative molecular similarity indices analysis (3D-QSAR/CoMSIA) study on a series of 90 reported irreversible inhibitors of FAAH sharing a piperazine-carboxamide scaffold. The model obtained was extensively validated (q2 = 0.734; r2 = 0.966; r2m = 0.723). Finally, based on the information derived from the contour maps we designed a series of 10 new compounds with high predicted FAAH inhibition (predicted pIC50 of the best-proposed compounds = 12.196; 12.416).
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Amidoidrolases/antagonistas & inibidores , Canabinoides/farmacologia , Relação Quantitativa Estrutura-Atividade , Inibidores Enzimáticos/farmacologia , Humanos , LigantesRESUMO
HER-2 and EGFR are biological targets related to the development of cancer and the discovery and/or development of a dual inhibitor could be a good strategy to design an effective drug candidate. In this study, analyses of the chemical properties of a group of substances having affinity for both HER-2 and EGFR were carried out with the aim of understanding the main factors involved in the interaction between these inhibitors and the biological targets. Comparative analysis of molecular interaction fields (CoMFA) and comparative molecular similarity index analysis (CoMSIA) techniques were applied on 63 compounds. From CoMFA analyses, we found for both HER-2 (r² calibration = 0.98 and q²cv = 0.83) and EGFR (r² calibration = 0.98 and q²cv = 0.73) good predictive models. Good models for CoMSIA technique have also been found for HER-2 (r² calibration = 0.92 and q²cv = 0.74) and EGFR (r² calibration = 0.97 and q²cv = 0.72). The constructed models could indicate some important characteristics for the inhibition of the biological targets. New compounds were proposed as candidates to inhibit both proteins. Therefore, this study may guide future projects for the development of new drug candidates for the treatment of breast cancer.
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Desenho de Fármacos , Receptores ErbB/química , Modelos Moleculares , Inibidores de Proteínas Quinases/química , Relação Quantitativa Estrutura-Atividade , Sítios de Ligação , Receptores ErbB/antagonistas & inibidores , Humanos , Conformação Molecular , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Ligação Proteica , Inibidores de Proteínas Quinases/farmacologia , Reprodutibilidade dos TestesRESUMO
The wide tissue distribution of the adrenergic ß3 receptor makes it a potential target for the treatment of multiple pathologies such as diabetes, obesity, depression, overactive bladder (OAB), and cancer. Currently, there is only one drug on the market, mirabegron, approved for the treatment of OAB. In the present study, we have carried out an extensive structure-activity relationship analysis of a series of 41 aryloxypropanolamine compounds based on three-dimensional quantitative structure-activity relationship (3D-QSAR) techniques. This is the first combined comparative molecular field analysis (CoMFA) and comparative molecular similarity index analysis (CoMSIA) study in a series of selective aryloxypropanolamines displaying anti-diabetes and anti-obesity pharmacological profiles. The best CoMFA and CoMSIA models presented values of r²ncv = 0.993 and 0.984 and values of r²test = 0.865 and 0.918, respectively. The results obtained were subjected to extensive external validation (q², r², r²m, etc.) and a final series of compounds was designed and their biological activity was predicted (best pEC50 = 8.561).
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Agonistas de Receptores Adrenérgicos beta 3/química , Fármacos Antiobesidade/química , Hipoglicemiantes/química , Propanolaminas/química , Agonistas de Receptores Adrenérgicos beta 3/farmacologia , Fármacos Antiobesidade/farmacologia , Sítios de Ligação , Desenho de Fármacos , Humanos , Hipoglicemiantes/farmacologia , Modelos Moleculares , Estrutura Molecular , Propanolaminas/farmacologia , Relação Quantitativa Estrutura-Atividade , Eletricidade EstáticaRESUMO
Farnesoid X receptor (FXR) is a nuclear receptor related to lipid and glucose homeostasis and is considered an important molecular target to treatment of metabolic diseases as diabetes, dyslipidemia, and liver cancer. Nowadays, there are several FXR agonists reported in the literature and some of it in clinical trials for liver disorders. Herein, a compound series was employed to generate QSAR models to better understand the structural basis for FXR activation by anthranilic acid derivatives (AADs). Furthermore, here we evaluate the inclusion of the standard deviation (SD) of EC50 values in QSAR models quality. Comparison between the use of experimental variance plus average values in model construction with the standard method of model generation that considers only the average values was performed. 2D and 3D QSAR models based on the AAD data set including SD values showed similar molecular interpretation maps and quality (Q2LOO, Q2(F2), and Q2(F3)), when compared to models based only on average values. SD-based models revealed more accurate predictions for the set of test compounds, with lower mean absolute error indices as well as more residuals near zero. Additionally, the visual interpretation of different QSAR approaches agrees with experimental data, highlighting key elements for understanding the biological activity of AADs. The approach using standard deviation values may offer new possibilities for generating more accurate QSAR models based on available experimental data.
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Receptores Citoplasmáticos e Nucleares/química , ortoaminobenzoatos/química , Humanos , Isoxazóis/química , Modelos Moleculares , Simulação de Acoplamento Molecular , Relação Quantitativa Estrutura-AtividadeRESUMO
In the present study, we have employed the ligand-based drug design technique, 3D-QSAR, through a comparative molecular field analysis (CoMFA) and a comparative molecular similarity indices analysis (CoMSIA) to determine the key factors for the plant growth promoting activity of brassinosteroids reported in literature, using the bean second-internode bioassay measured on two groups of compounds with different molar concentrations. This is the first 3D-QSAR study using the second internode elongation as biological activity. These results provide useful ideas for the design of new molecules, which could be explored in the future to identify novel vegetable growth promoters with similar or greater biological activity than natural brassinosteroids. The reliability of this study was supported by the robust statistical parameters obtained from CoMFA (Model A, r²pred = 0.751; Model B, r²pred = 0.770) and CoMSIA (Model A, r²pred = 0.946; Model B, r²pred = 0.923) analysis.
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Brassinosteroides/metabolismo , Relação Quantitativa Estrutura-Atividade , Verduras/crescimento & desenvolvimento , Verduras/metabolismoRESUMO
AIM: Chagas disease is endemic in Latin America and no effective treatment is available. Efforts in drug research have focused on several enzymes from Trypanosoma cruzi, among which cruzain is a validated pharmacological target. METHODOLOGY: Chemometric analyses were performed on the data set using the hologram quantitative structure-activity relationship, comparative molecular field analysis and comparative molecular similarity index analysis methods. Docking simulations were executed using the crystallographic structure of cruzain in complex with a benzimidazole inhibitor. The top-scoring enzyme-inhibitor complexes were selected for the development of the 3D quantitative structure-activity relationship (QSAR) models and to assess the inhibitor binding modes and intermolecular interactions. RESULTS: Benzimidazole derivatives as cruzain inhibitors were used in molecular docking and QSAR studies. Significant statistical indicators were obtained, and the best models demonstrated high predictive ability for an external test set (r 2pred = 0.65, 0.94 and 0.82 for hologram QSAR, comparative molecular field analysis and comparative molecular similarity index analysis, respectively). Additionally, the graphical information of the chemometric analyses demonstrated substantial complementarity with the enzyme-binding site. CONCLUSION: These results demonstrate the relevance of the QSAR models to guide the design of structurally related benzimidazole derivatives with improved potency.
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Benzimidazóis/farmacologia , Doença de Chagas/tratamento farmacológico , Inibidores de Cisteína Proteinase/farmacologia , Proteínas de Protozoários/antagonistas & inibidores , Tripanossomicidas/farmacologia , Trypanosoma cruzi/efeitos dos fármacos , Benzimidazóis/síntese química , Benzimidazóis/química , Benzimidazóis/metabolismo , Sítios de Ligação , Doença de Chagas/metabolismo , Cisteína Endopeptidases/metabolismo , Inibidores de Cisteína Proteinase/síntese química , Inibidores de Cisteína Proteinase/química , Inibidores de Cisteína Proteinase/metabolismo , Descoberta de Drogas , Humanos , Modelos Moleculares , Simulação de Acoplamento Molecular , Estrutura Molecular , Ligação Proteica , Proteínas de Protozoários/metabolismo , Relação Quantitativa Estrutura-Atividade , América do Sul , Tripanossomicidas/síntese química , Tripanossomicidas/química , Tripanossomicidas/metabolismo , Trypanosoma cruzi/metabolismoRESUMO
The ß3 adrenergic receptor is raising as an important drug target for the treatment of pathologies such as diabetes, obesity, depression, and cardiac diseases among others. Several attempts to obtain selective and high affinity ligands have been made. Currently, Mirabegron is the only available drug on the market that targets this receptor approved for the treatment of overactive bladder. However, the FDA (Food and Drug Administration) in USA and the MHRA (Medicines and Healthcare products Regulatory Agency) in UK have made reports of potentially life-threatening side effects associated with the administration of Mirabegron, casting doubts on the continuity of this compound. Therefore, it is of utmost importance to gather information for the rational design and synthesis of new ß3 adrenergic ligands. Herein, we present the first combined 2D-QSAR (two-dimensional Quantitative Structure-Activity Relationship) and 3D-QSAR/CoMSIA (three-dimensional Quantitative Structure-Activity Relationship/Comparative Molecular Similarity Index Analysis) study on a series of potent ß3 adrenergic agonists of indole-alkylamine structure. We found a series of changes that can be made in the steric, hydrogen-bond donor and acceptor, lipophilicity and molar refractivity properties of the compounds to generate new promising molecules. Finally, based on our analysis, a summary and a regiospecific description of the requirements for improving ß3 adrenergic activity is given.
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Agonistas de Receptores Adrenérgicos beta 3/química , Agonistas de Receptores Adrenérgicos beta 3/farmacologia , Indóis/química , Indóis/farmacologia , Relação Quantitativa Estrutura-Atividade , Desenho de Fármacos , Humanos , Ligação de Hidrogênio , Ligantes , Modelos Moleculares , Conformação Molecular , Estrutura MolecularRESUMO
The preceding years have brought an exponential increase in our understanding of the endocannabinoid system (ECS), including the knowledge of CB1 and CB2 cannabinoid receptors, endocannabinoids, and the enzymes that synthesize and degrade endocannabinoids. Among these ECS components CB2 receptors have been the subject of considerable attention, primarily due to their promising therapeutic potential to treat numerous pathologies while avoiding the adverse psychotropic effects that can accompany CB1 receptor-based therapies. Recently, our research group has reported a new series of non-cytotoxic benzo[d]imidazoles and benzo[b]thiophenes displaying high CB2/CB1 selectivity index. In order to investigate the structural requirements for CB2 ligands and to derive a predictive model that can be used for the design of novel selective CB2 ligands, a three-dimensional quantitative structure-activity relationship (3D-QSAR) study was performed on the above mentioned chemical series employing comparative molecular field analysis (CoMFA) and comparative molecular similarity index analysis (CoMSIA) techniques. The CoMFA and CoMSIA models displayed high external predictability (rpred2 0.919 and 0.908) and good statistical robustness. Valuable information regarding the steric, electrostatic and hydrophobic properties of the molecules was obtained, and several modifications around both heterocycles were evaluated with the aim to generate new promising series of benzo[d]imidazoles and benzo[b]thiophenes derivatives displaying high CB2 selectivity and low toxicity.
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Benzimidazóis/química , Receptor CB2 de Canabinoide/química , Tiofenos/química , Canabinoides/química , Interações Hidrofóbicas e Hidrofílicas , Ligantes , Modelos Moleculares , Relação Quantitativa Estrutura-Atividade , Receptor CB1 de Canabinoide/química , Eletricidade EstáticaRESUMO
Studies have showed that there are many biological targets related to the cancer treatment, for example, TGF type I receptor (TGF-ßRI or ALK5). The ALK5 inhibition is a strategy to treat some types of cancer, such as breast, lung, and pancreas. Here, we performed CoMFA and CoMSIA studies for 70 ligands with ALK5 inhibition. The internal validation for both models (q(2)LOO = 0.887 and 0.822, respectively) showed their robustness, while the external validations showed their predictive power (CoMFA: r(2)test = 0.998; CoMSIA: r(2)test = 0.975). After all validations, CoMFA and CoMSIA maps indicated physicochemical evidences on the main factors involved in the interaction between bioactive ligands and ALK5. Therefore, these results suggest molecular modifications to design new ALK5 inhibitors.
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Ligantes , Modelos Moleculares , Proteínas Serina-Treonina Quinases/química , Receptores de Fatores de Crescimento Transformadores beta/química , Antineoplásicos/química , Antineoplásicos/farmacologia , Sítios de Ligação , Simulação por Computador , Desenho de Fármacos , Humanos , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Ligação Proteica , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Proteínas Serina-Treonina Quinases/metabolismo , Relação Quantitativa Estrutura-Atividade , Receptor do Fator de Crescimento Transformador beta Tipo I , Receptores de Fatores de Crescimento Transformadores beta/antagonistas & inibidores , Receptores de Fatores de Crescimento Transformadores beta/metabolismo , Reprodutibilidade dos TestesRESUMO
The dopamine hypothesis states that decreased dopaminergic neurotransmission reduces schizophrenia symptoms. Neurokinin-3 receptor (NK3) antagonists reduce dopamine release and have shown positive effects in pre-clinical and clinical trials. We employed 2D and 3D-QSAR analysis on a series of 40 non-peptide NK3 antagonists. Multivariate statistical analysis, PCA and HCA, were performed to rational training/test set splitting and PLS regression was employed to construct all QSAR models. We constructed one highly predictive CoMFA model (q(2)= 0.810 and r(2)= 0.929) and acceptable HQSAR and CoMSIA models (HQSAR q(2)= 0.644 and r(2)= 0.910; CoMSIA q(2)= 0.691, r(2)= 0.911). The three different techniques provided convergent physicochemical results. All models indicate cyclopropane, piperidine and di-chloro-phenyl ring attached to cyclopropane ring and also the amide group attached to the piperidine ring could play an important role in ligand-receptor interactions. These findings may contribute to develop potential NK3 receptor antagonists for schizophrenia.
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Relação Quantitativa Estrutura-Atividade , Receptores da Neurocinina-3/antagonistas & inibidores , Esquizofrenia/tratamento farmacológico , Ciclopropanos/química , Humanos , Piperidinas/químicaRESUMO
A major problem today is bacterial resistance to antibiotics and the small number of new therapeutic agents approved in recent years. The development of new antibiotics capable of acting on new targets is urgently required. The filamenting temperature-sensitive Z (FtsZ) bacterial protein is a key biomolecule for bacterial division and survival. This makes FtsZ an attractive new pharmacological target for the development of antibacterial agents. There have been several attempts to develop ligands able to inhibit FtsZ. Despite the large number of synthesized compounds that inhibit the FtsZ protein, there are no quantitative structure-activity relationships (QSAR) that allow for the rational design and synthesis of promising new molecules. We present the first 3D-QSAR study of a large and diverse set of molecules that are able to inhibit the FtsZ bacterial protein. We summarize a set of chemical changes that can be made in the steric, electrostatic, hydrophobic and donor/acceptor hydrogen-bonding properties of the pharmacophore, to generate new bioactive molecules against FtsZ. These results provide a rational guide for the design and synthesis of promising new antibacterial agents, supported by the strong statistical parameters obtained from CoMFA (r(2)(pred) = 0.974) and CoMSIA (r(2)(pred) = 0.980) analyses.