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1.
Bioorg Chem ; 107: 104620, 2021 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-33454509

RESUMO

Xanthine oxidase (XO) has been primarily targeted for the development of anti-hyperuriciemic /anti-gout agents as it catalyzes the conversion of xanthine and hypoxanthine into uric acid. XO overexpression in various cancer is very well correlated due to reactive oxygen species (ROS) production and metabolic activation of carcinogenic substances during the catalysis. Herein, we report the design and synthesis of a series of 3,5-diaryl-4,5-dihydro-1H-pyrazole carbaldehyde derivatives (2a-2x) as xanthine oxidase inhibitors (XOIs). A docking model was developed for the prediction of XO inhibitory activity of our novel compounds. Furthermore, our compounds anticancer activity results in low XO expression and XO-harboring cancer cells both in 2D and 3D-culture models are presented and discussed. Among the array of synthesized compounds, 2b and 2m emerged as potent XO inhibitors having IC50 values of 9.32 ± 0.45 µM and 10.03 ± 0.43 µM, respectively. Both compounds induced apoptosis, halted the cell cycle progression at the G1 phase, elevated ROS levels, altered mitochondrial membrane potential, and inhibited antioxidant enzymes. The levels of miRNA and expression of redox sensors in cells were also altered due to increase oxidative stress induced by our compounds. Compounds 2b and 2m hold a great promise for further development of XOIs for the treatment of XO-harboring tumors.

2.
Life Sci ; : 118676, 2020 Oct 28.
Artigo em Inglês | MEDLINE | ID: mdl-33129880

RESUMO

Angiotensin-converting enzyme 2 (ACE 2) is a membrane-bound enzyme that cleaves angiotensin II (Ang II) into angiotensin (1-7). It also serves as an important binding site for SARS-CoV-2, thereby, facilitating viral entry into target host cells. ACE 2 is abundantly present in the intestine, kidney, heart, lungs, and fetal tissues. Fetal ACE 2 is involved in myocardium growth, lungs and brain development. ACE 2 is highly expressed in pregnant women to compensate preeclampsia by modulating angiotensin (1-7) which binds to the Mas receptor, having vasodilator action and maintain fluid homeostasis. There are reports available on Zika, H1N1 and SARS-CoV where these viruses have shown to produce fetal defects but very little is known about SARS-CoV-2 involvement in pregnancy, but it might have the potential to interact with fetal ACE 2 and enhance COVID-19 transmission to the fetus, leading to fetal morbidity and mortality. This review sheds light on a path of SARS-CoV-2 transmission risk in pregnancy and its possible link with fetal ACE 2.

3.
Bioorg Chem ; 104: 104326, 2020 11.
Artigo em Inglês | MEDLINE | ID: mdl-33142431

RESUMO

SARS-CoV-2 (COVID-19) epidemic has created an unprecedented medical and economic crisis all over the world. SARS-CoV-2 is found to have more contagious character as compared to MERS-CoV and is spreading in a very fast manner all around the globe. It has affected over 31 million people all over the world till date. This virus shares around 80% of genome similarity with SARS-CoV. In this perspective, we have explored three major targets namely; SARS-CoV-2 spike (S) protein, RNA dependent RNA polymerase, and 3CL or Mpro Protease for the inhibition of SARS-CoV-2. These targets have attracted attention of the medicinal chemists working on computer-aided drug design in developing new small molecules that might inhibit these targets for combating COVID-19 disease. Moreover, we have compared the similarity of these target proteins with earlier reported coronavirus (SARS-CoV). We have observed that both the coronaviruses share around 80% similarity in their amino acid sequence. The key amino acid interactions which can play a crucial role in designing new small molecule inhibitors against COVID-19 have been reported in this perspective. Authors believe that this study will help the medicinal chemists to understand the key amino acids essential for interactions at the active site of target proteins in SARS-CoV-2, based on their similarity with earlier reported viruses. In this review, we have also described the lead molecules under various clinical trials for their efficacy against COVID-19.

4.
J Biomol Struct Dyn ; : 1-13, 2020 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-32666910

RESUMO

Despite the intensive research efforts towards antiviral drug against COVID-19, no potential drug or vaccines has not yet discovered. Initially, the binding site of COVID-19 main protease was predicted which located between regions 2 and 3. Structure-based virtual screening was performed through a hierarchal mode of elimination technique after generating a grid box. This led to the identification of five top hit molecules that were selected on the basis of docking score and visualization of non-bonding interactions. The docking results revealed that the hydrogen bonding and hydrophobic interactions are the major contributing factors in the stabilization of complexes. The docking scores were found between -7.524 and -6.711 kcal/mol indicating strong ligand-protein interactions. Amino acid residues Phe140, Leu141, Gly143, Asn142, Thr26, Glu166 and Thr190 (hydrogen bonding interactions) and Phe140, Cys145, Cys44, Met49, Leu167, Pro168, Met165, Val42, Leu27 and Ala191 (hydrophobic interactions) formed the binding pocket of COVID-19 main protease. From identified hits, ZINC13144609 and ZINC01581128 were selected for atomistic MD simulation and density functional theory calculations. MD simulation results confirm that the protein interacting with both hit molecules is stabilized in the chosen POPC lipid bilayer membrane. The presence of lowest unoccupied molecular orbital (LUMO) and highest occupied molecular orbital (HOMO) in the hydrophobic region of the hit molecules leads to favorable ligand-protein contacts. The calculated pharmacokinetic descriptors were found to be in their acceptable range and therefore confirming their drug-like properties. Hence, the present investigation can serve as the basis for designing and developing COVID-19 inhibitors. Communicated by Ramaswamy H. Sarma.

5.
ACS Nano ; 14(7): 7760-7782, 2020 07 28.
Artigo em Inglês | MEDLINE | ID: mdl-32571007

RESUMO

The current global health threat by the novel coronavirus disease 2019 (COVID-19) requires an urgent deployment of advanced therapeutic options available. The role of nanotechnology is highly relevant to counter this "virus" nano enemy. Nano intervention is discussed in terms of designing effective nanocarriers to counter the conventional limitations of antiviral and biological therapeutics. This strategy directs the safe and effective delivery of available therapeutic options using engineered nanocarriers, blocking the initial interactions of viral spike glycoprotein with host cell surface receptors, and disruption of virion construction. Controlling and eliminating the spread and reoccurrence of this pandemic demands a safe and effective vaccine strategy. Nanocarriers have potential to design risk-free and effective immunization strategies for severe acute respiratory syndrome coronavirus 2 vaccine candidates such as protein constructs and nucleic acids. We discuss recent as well as ongoing nanotechnology-based therapeutic and prophylactic strategies to fight against this pandemic, outlining the key areas for nanoscientists to step in.


Assuntos
Infecções por Coronavirus/prevenção & controle , Vacinação em Massa/métodos , Nanotecnologia/métodos , Pandemias/prevenção & controle , Pneumonia Viral/prevenção & controle , Vacinas Virais/uso terapêutico , Infecções por Coronavirus/imunologia , Infecções por Coronavirus/terapia , Infecções por Coronavirus/virologia , Humanos , Vacinação em Massa/efeitos adversos , Pneumonia Viral/imunologia , Pneumonia Viral/terapia , Pneumonia Viral/virologia , Vacinas Virais/imunologia
6.
Curr Drug Targets ; 21(9): 864-891, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32156235

RESUMO

Heterocyclic compounds play a significant role in various biological processes of the human body and many of them are in clinical use due to their diverse, chemical and biological properties. Among these, indole is one of the most promising pharmacologically active molecules. Due to its chemical reactivity, indole has been willingly modified to obtain a variety of new lead molecules, which has been successfully utilized to obtained novel drug candidates for the treatment of different pharmacological diseases. Indole-based compounds such as vincristine (anticancer), reserpine (antihypertensive), amedalin (antidepressant) and many more describe the medicinal and pharmacological importance of the indole in uplifting human life. In this review, we compiled various reports on indole derivatives and their biological significance, including antifungal, antiprotozoal, antiplatelet, anti- Alzheimer's, anti-Parkinson's, antioxidant and anticancer potential from 2015 onwards. In addition, structure-activity relationship studies of the different derivatives have been included. We have also discussed novel synthetic strategies developed during this period for the synthesis of different indole derivatives. We believe that this review article will provide comprehensive knowledge about the medicinal importance of indoles and will help in the design and synthesis of novel indole-based molecules with high potency and efficacy.

7.
Bioorg Chem ; 94: 103409, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31732194

RESUMO

In the quest to ameliorate the camptothecin (CPT) downsides, we expedite to search for stable non-CPT analogues among 11 motifs of pyrazoloquinazolines reported. E-pharmacophore drug design approach helped filtering out pyrazolo[1,5-c]quinazolines as Topoisomerase I (TopoI) 'interfacial' inhibitors. Three compounds, 3c, 3e, and 3l were shown to be potent non-intercalating inhibitors of TopoI specifically and showed cancer cell-specific cytotoxicity in lung, breast and colon cancer cell lines. The compounds induced cell cycle arrest at S-phase, mitochondrial cell death pathway and modulated oxidative stress in cancer cells. Furthermore, a preliminary study was conducted to explore the feasibility of these compounds to be developed as dual TopoI-HDAC1 (histone deacetylase 1) inhibitors (4a) to combat resistance. Compound 4a was found to possess dual inhibitory capabilities in-vitro. Cytotoxic potential of 4a was found to be significantly higher than parent compound in 2D as well as 3D cancer cell models. Probable binding modes of 4a with TopoI and HDAC1 active sites were examined by molecular modelling.

8.
Bioorg Chem ; 93: 103314, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31590041

RESUMO

A series of pyrazolo[1,5-c]quinazolines as EGFR inhibitors was designed and synthesized by highly efficient and novel multicomponent route involving Pd-catalyzed tandem one-pot four-component reaction. The reaction proceeds with good functional group tolerance under a simple condition with excellent regioselectivity and high efficiency. Target compounds were screened against cancer cell lines MDA-MB-231, A549 and H1299. Of these, 9b and 10b exhibited superior anticancer activity (IC50 < 2.5 µM) to erlotinib and gefitinib. Synthetics were able to inhibit EGFR mediated kinase activity, induced ROS in cancer cells promoting mitochondrial mediated apoptosis via halting cell cycle progression at G1 phase.


Assuntos
Receptores ErbB/antagonistas & inibidores , Paládio/química , Inibidores de Proteínas Quinases/síntese química , Pirazóis/química , Quinazolinas/química , Apoptose/efeitos dos fármacos , Sítios de Ligação , Catálise , Domínio Catalítico , Linhagem Celular Tumoral , Desenho de Fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Receptores ErbB/metabolismo , Cloridrato de Erlotinib/química , Cloridrato de Erlotinib/metabolismo , Cloridrato de Erlotinib/farmacologia , Pontos de Checagem da Fase G1 do Ciclo Celular/efeitos dos fármacos , Humanos , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Simulação de Acoplamento Molecular , Inibidores de Proteínas Quinases/metabolismo , Inibidores de Proteínas Quinases/farmacologia , Pirazóis/metabolismo , Pirazóis/farmacologia , Quinazolinas/metabolismo , Quinazolinas/farmacologia , Espécies Reativas de Oxigênio/metabolismo , Relação Estrutura-Atividade
9.
Eur J Med Chem ; 182: 111644, 2019 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-31493745

RESUMO

The emergence of drug resistance in infectious microbial strains can be overcome by development of novel drug molecules against unexploited microbial target. The success of Bedaquiline in recent years, as FoF1 ATP synthase inhibitor against XDR and MDR mycobacterium strains, has resulted in further exploration to identify more potent and safe drug molecules against resistant strains. FoF1 ATP synthase is the main energy production enzyme in almost all eukaryotes and prokaryotes. Development of bacterial ATP synthase inhibitors is a safe approach, without causing harm to mammalian cells due to structural difference between bacterial and mammalian ATP synthase target sites. This review emphasizes on providing the structural insights for FoF1 ATP synthase of different prokaryotes and will help in the design of new potent antimicrobial agents with better efficacy. Further, applications of synthetic and natural active antimicrobial ATP synthase inhibitors, reported by different research groups are summarized. Their SAR and mode of actions are also analysed.


Assuntos
Antibacterianos/farmacologia , Inibidores Enzimáticos/farmacologia , Mycobacterium/efeitos dos fármacos , ATPases Translocadoras de Prótons/antagonistas & inibidores , Animais , Antibacterianos/química , Relação Dose-Resposta a Droga , Inibidores Enzimáticos/química , Humanos , Testes de Sensibilidade Microbiana , Estrutura Molecular , Mycobacterium/enzimologia , ATPases Translocadoras de Prótons/metabolismo , Relação Estrutura-Atividade
10.
J Biomol Struct Dyn ; 37(12): 3226-3244, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-30124114

RESUMO

In spite of various research investigations towards anti-depressant drug discovery program, no one drug has not yet launched last 20 years. Corticotropin-releasing factor-1 (CRF-1) is one of the most validated targets for the development of antagonists against depression, anxiety and post-traumatic stress disorders. Various research studies suggest that pyrazinone based CRF-1 receptor antagonists were found to be highly potent and efficacious. In this research investigation, we identified the pharmacophore and binding pattern through 2D and 3D-QSAR and molecular docking respectively. Molecular dynamics studies were also performed to explore the binding pattern recognition. We establish the relationship between activity and pharmacophoric features to design new potent compounds. The best 2D-QSAR model was generated through multiple linear regression method with r2 value of 0.97 and q2 value of 0.89. Also 3D-QSAR model was obtained through k-nearest neighbor molecular field analysis method with q2 value of 0.52 and q2_se value of 0.36. Molecular docking and binding energy were also evaluated to define binding patterns and pharmacophoric groups, including (i) hydrogen bond with residue Asp284, Glu305 and (ii) π-π stacking with residue Trp9. Compound 11i has the highest binding affinity compared to reference compounds, so this compound could be a potent drug for stress related disorders. Most of the compounds, including reference compounds were found within acceptable range of physicochemical parameters. These observations could be provided the leads for the design and optimization of novel CRF-1 receptor antagonists. Communicated by Ramaswamy H. Sarma.


Assuntos
Antidepressivos/farmacologia , Hormônio Liberador da Corticotropina/metabolismo , Receptores de Hormônio Liberador da Corticotropina/metabolismo , Sítios de Ligação , Desenho de Fármacos , Humanos , Ligação de Hidrogênio , Simulação de Acoplamento Molecular/métodos , Relação Quantitativa Estrutura-Atividade , Análise de Regressão
11.
Mini Rev Med Chem ; 19(6): 510-526, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30338737

RESUMO

After restricting the proliferation of CD4+T cells, Human Immunodeficiency Virus (HIV), infection persists at a very fast rate causing Acquired Immunodeficiency Syndrome (AIDS). This demands the vigorous need of suitable anti-HIV agents, as existing medicines do not provide a complete cure and exhibit drawbacks like toxicities, drug resistance, side-effects, etc. Even the introduction of Highly Active Antiretroviral Therapy (HAART) failed to combat HIV/AIDS completely. The major breakthrough in anti-HIV discovery was marked with the discovery of raltegravir in 2007, the first integrase (IN) inhibitor. Thereafter, the discovery of elvitegravir, a quinolone derivative emerged as the potent HIV-IN inhibitor. Though many more classes of different drugs that act as anti-HIV have been identified, some of which are under clinical trials, but the recent serious focus is still laid on quinoline and its analogues. In this review, we have covered all the quinoline-based derivatives that inhibit various targets and are potential anti-HIV agents in various phases of the drug discovery.


Assuntos
Fármacos Anti-HIV/química , Fármacos Anti-HIV/farmacologia , Descoberta de Drogas , Infecções por HIV/tratamento farmacológico , HIV/efeitos dos fármacos , Quinolonas/química , Quinolonas/farmacologia , Animais , Fármacos Anti-HIV/uso terapêutico , Descoberta de Drogas/métodos , HIV/enzimologia , Integrase de HIV/química , Integrase de HIV/metabolismo , Inibidores de Integrase de HIV/química , Inibidores de Integrase de HIV/farmacologia , Inibidores de Integrase de HIV/uso terapêutico , Humanos , Modelos Moleculares , Quinolonas/uso terapêutico
12.
Chem Commun (Camb) ; 54(82): 11530-11533, 2018 Oct 11.
Artigo em Inglês | MEDLINE | ID: mdl-30137112

RESUMO

Synthesis of pyrazolo[1,5-c]quinazolines from four easily available precursors is presented through a one-pot tricyclic Pd(ii)/Ag(i) relay catalysis. The bimetallic relay cascade forges five new chemical bonds by concatenating six discrete chemical steps. The relay catalysis enables four-component assembly of pyrazolo[1,5-c]quinazolines that selectively inhibit EGFR, exhibit apoptosis through the ROS-induced mitochondrial-mediated pathway, and arrest the cell cycle at the G1 phase.

13.
Eur J Clin Pharmacol ; 74(10): 1291-1298, 2018 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-29938344

RESUMO

PURPOSE: Cyclophosphamide and doxorubicin (adjuvant chemotherapy) are commonly used to treat breast cancer patients. Variation in the genes involved in pharmacodynamics and pharmacokinetics of these drugs plays an important role in prediction of drug response and survival. The present study was carried out with an aim to evaluate the variation in all the genes involved in pharmacokinetic and pharmacodynamics pathways of cyclophosphamide and doxorubicin, and correlate specific variants with disease outcome in breast cancer patients from the Malwa region of Punjab. METHODS: A total of 250 confirmed breast cancer patients were involved in the study. Genotyping was performed on an Illumina Infinium HD assay platform using a Global Screening Array (GSA) microchip. GenomeStudio (Illumina, Inc.) was used for data preprocessing and a p value less than or equal to 5 × 10-8 was considered statistically significant. To rule out the influence of confounding risk factors, a step-wise multivariate regression analysis was carried out to evaluate the association of genotype with overall clinical outcome. RESULTS: Two gene variants, CYP2C19 (G681A) and ALDH1A1*2 (17 bp deletion), were found to be significantly associated with the disease outcome, including overall survival, recurrence and metastasis, in breast cancer patients on adjuvant therapy. Both these genes are involved in the pharmacokinetics of cyclophosphamide. However, none of the variants in the genes involved in pharmacokinetics and pharmacodynamics of doxorubicin were found to have any significant impact on disease outcome in the studied group. CONCLUSION: CYP2C19 (G681A) variant and ALDH1A1*2 emerged as two important biomarkers associated with bad outcome in breast cancer patients on adjuvant therapy.


Assuntos
Aldeído Desidrogenase/genética , Neoplasias da Mama/tratamento farmacológico , Ciclofosfamida/administração & dosagem , Citocromo P-450 CYP2C19/genética , Doxorrubicina/administração & dosagem , Adulto , Idoso , Antibióticos Antineoplásicos/administração & dosagem , Antibióticos Antineoplásicos/farmacocinética , Antineoplásicos Alquilantes/administração & dosagem , Antineoplásicos Alquilantes/farmacocinética , Biomarcadores Tumorais/genética , Neoplasias da Mama/genética , Quimioterapia Adjuvante/métodos , Ciclofosfamida/farmacocinética , Doxorrubicina/farmacocinética , Feminino , Genótipo , Humanos , Índia , Análise em Microsséries/métodos , Pessoa de Meia-Idade , Análise de Regressão , Retinal Desidrogenase , Taxa de Sobrevida , Resultado do Tratamento
14.
Arch Pharm (Weinheim) ; 351(6): e1800023, 2018 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-29737542

RESUMO

The design and synthesis of dihydropyrazolo[1,5-c]quinazolines (1a-h) as human topoisomerase II (TopoII) catalytic inhibitors are reported. The compounds were investigated for their antiproliferative activity against the C6 rat glial cell line. Two compounds, 1b and 1h, were found to be potent cytotoxic agents against glioma cells and exerted selective TopoII inhibitory activity. Furthermore, the compounds induced alterations in reactive oxygen species levels as measured by DCFDA assay and were found to induce cell cycle arrest at the G1 phase at lower concentrations and profound apoptosis at higher concentrations. The interaction of selected investigational molecules with TopoII was further corroborated by molecular modeling.


Assuntos
Antineoplásicos/farmacologia , Glioma/tratamento farmacológico , Quinazolinas/farmacologia , Inibidores da Topoisomerase II/farmacologia , Animais , Antineoplásicos/síntese química , Antineoplásicos/química , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , DNA Topoisomerases Tipo II/efeitos dos fármacos , DNA Topoisomerases Tipo II/metabolismo , Relação Dose-Resposta a Droga , Pontos de Checagem da Fase G1 do Ciclo Celular/efeitos dos fármacos , Glioma/enzimologia , Humanos , Modelos Moleculares , Quinazolinas/síntese química , Quinazolinas/química , Ratos , Espécies Reativas de Oxigênio/metabolismo , Inibidores da Topoisomerase II/síntese química , Inibidores da Topoisomerase II/química
15.
Curr Top Med Chem ; 18(31): 2720-2730, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30659538

RESUMO

BACKGROUND: Malaria, one of the World's biggest billers' is on the schedule for biomedical research and public health policies. The introduction of the artemisinin, a Chinese traditional drug from Artemisia annua is a revolution in the treatment of malaria. Artemisinin-based combination treatment (ACT) is considered to be the best strategy for uncomplicated Falciparum malaria. The presence of 1,2,4-trioxane system in artemisinin is responsible for its antimalarial activity. METHODS: In this study, twenty-nine analogues of artemisinin were taken into account for QSAR studies along with artemisinin. The most active analogue of artemisinin 21 was energy minimized. All the structures were prepared from the active conformer 21 and energy was minimized to the stable state using MMFF94 force field using ChemBioDraw-12. Genetic Algorithm is used to decide the descriptors best required for the model generation. The test set and training set division were done by using hierarchal clustering module available with NCSS statistical software. RESULTS AND CONCLUSION: The antimalarial activity of the artemisinin and its substituted analogues has been analyzed through the multiple linear regression (MLR) using various physiochemical and structural descriptors obtained from PADEL software. The models were prepared using the Sigma Plot version 11. The calculated 2D autocorrelation descriptors and the MLR model suggest that artemisinin and its analogues hold the scope in the optimization of antimalarial activity.


Assuntos
Antimaláricos/farmacologia , Artemisia annua/química , Artemisininas/farmacologia , Medicamentos de Ervas Chinesas/farmacologia , Plasmodium falciparum/efeitos dos fármacos , Relação Quantitativa Estrutura-Atividade , Algoritmos , Antimaláricos/síntese química , Antimaláricos/química , Artemisininas/síntese química , Artemisininas/química , Relação Dose-Resposta a Droga , Medicamentos de Ervas Chinesas/síntese química , Medicamentos de Ervas Chinesas/química , Modelos Lineares , Conformação Molecular , Simulação de Acoplamento Molecular , Testes de Sensibilidade Parasitária , Software
16.
Curr Top Med Chem ; 18(32): 2800-2815, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30747071

RESUMO

The failure of the Integrase Strand Transfer Inhibitors (INSTIs) due to the mutations occurring at the catalytic site of HIV integrase (IN) has led to the design of allosteric integrase inhibitors (ALLINIs). Lens epithelium derived growth factor (LEDGF/p75) is the host cellular cofactor which helps chaining IN to the chromatin. The protein-protein interactions (PPIs) were observed at the allosteric site (LEDGF/p75 binding domain) between LEDGF/p75 of the host cell and IN of virus. In recent years, many small molecules such as CX04328, CHIBA-3053 and CHI-104 have been reported as LEDGF/p75-IN interaction inhibitors (LEDGINs). LEDGINs have emerged as promising therapeutics to halt the PPIs by binding at the interface of both the proteins. In the present work, we correlated the docking scores for the reported LEDGINs containing quinoline scaffold with the in vitro biological data. The hierarchal clustering method was used to divide the compounds into test and training set. The robustness of the generated model was validated by q2 and r2 for the predicted set of compounds. The generated model between the docking score and biological data was assessed to predict the activity of the hits (quinoline scaffold) obtained from virtual screening of LEDGINs providing their structureactivity relationships to aim for the generation of potent agents.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/antagonistas & inibidores , Simulação por Computador , Inibidores de Integrase de HIV/farmacologia , Integrase de HIV/metabolismo , Quinolinas/farmacologia , Receptor de Fator de Crescimento Neural/antagonistas & inibidores , Bibliotecas de Moléculas Pequenas/farmacologia , Fatores de Transcrição/antagonistas & inibidores , Proteínas Adaptadoras de Transdução de Sinal/química , Sítio Alostérico/efeitos dos fármacos , Avaliação Pré-Clínica de Medicamentos , Integrase de HIV/química , Inibidores de Integrase de HIV/química , Humanos , Modelos Moleculares , Estrutura Molecular , Ligação Proteica/efeitos dos fármacos , Quinolinas/química , Receptor de Fator de Crescimento Neural/química , Bibliotecas de Moléculas Pequenas/química , Fatores de Transcrição/química
17.
J Biomol Struct Dyn ; 36(7): 1691-1712, 2018 May.
Artigo em Inglês | MEDLINE | ID: mdl-28521603

RESUMO

Despite the various research efforts toward the treatment of stress-related disorders, the drug has not yet launched last 20 years. Corticotropin releasing factor-1 receptor antagonists have been point of great interest in stress-related disorders. In the present study, we have selected benzazole scaffold-based compounds as corticotropin releasing factor-1 antagonists and performed 2D and 3D QSAR studies to identify the structural features to elucidating the binding mechanism prediction. The best 2D QSAR model was obtained through multiple linear regression method with r2 value of .7390, q2 value of .5136 and pred_r2 (predicted square correlation coefficient) value of .88. The contribution of 2D descriptor, T_2_C_1 was 60% (negative contribution) and 4pathClusterCount was 40.24% (positive contribution) in enhancing the activity. Also 3D QSAR model was statistically significant with q2 value of .9419 and q2_se (standard error of internal validation) value of .19. Statistical parameters results prove the robustness and significance of both models. Further, molecular docking and pharmacokinetic analysis was performed to explore the scope of investigation. Docking results revealed that the all benzazole compounds show hydrogen bonding with residue Asn283 and having same hydrophobic pocket (Phe286, Leu213, Ile290, Leu287, Phe207, Arg165, Leu323, Tyr327, Phe284, and Met206). Compound B14 has higher activity compare to reference molecules. Most of the compounds were found within acceptable range for pharmacokinetic parameters. This work provides the extremely useful leads for structural substituents essential for benzimidazole moiety to exhibit antagonistic activity against corticotropin releasing factor-1 receptors.


Assuntos
Benzimidazóis/química , Hormônio Liberador da Corticotropina/antagonistas & inibidores , Hormônio Liberador da Corticotropina/química , Sítios de Ligação , Simulação por Computador , Desenho de Fármacos , Ligação de Hidrogênio , Interações Hidrofóbicas e Hidrofílicas , Simulação de Acoplamento Molecular/métodos , Ligação Proteica , Relação Quantitativa Estrutura-Atividade
18.
Med Res Rev ; 38(4): 1073-1125, 2018 07.
Artigo em Inglês | MEDLINE | ID: mdl-28672082

RESUMO

Almost all drug molecules become the substrates for oxidoreductase enzymes, get metabolized into more hydrophilic products and eliminated from the body. These metabolites sometime may be more potent, active, inactive, or toxic in nature compared to parent molecule. Xanthine oxidoreductase and aldehyde oxidase belong to molybdenum containing family and are well characterized for their structures and functions, in particular to their ability to oxidize/hydroxylate the xenobiotics. Their upregulated clinical levels causing oxidative stress are associated with pathways either directly involved in the progression of diseases, gout, or indirectly with the succession of other diseases such as diabetes, cancer, etc. Herein, we have put forth a comprehensive review on the xanthine and aldehyde oxidases pertaining to their structures, functions, pathophysiological role, and a comparative analysis of structural insights of xanthine and aldehyde oxidases' binding domains with endogenous ligands or inhibitors. Though both the enzymes are molybdenum containing and are likely to share some common pathways and interact with inhibitors in a similar manner but we have focused on structural prerequisites for inhibitor specificity to both the enzymes keeping in view of the existing X-ray structures. This review also provides futuristic implications in the design of inhibitors derived from inorganic complexes or small organic molecules considering the spatial features and structural insights of both the enzymes.


Assuntos
Aldeído Oxidase/química , Fígado/efeitos dos fármacos , Molibdênio/química , Xantina Desidrogenase/química , Animais , Técnicas Biossensoriais , Domínio Catalítico , Cristalografia por Raios X , Humanos , Concentração Inibidora 50 , Cinética , Ligantes , Fígado/metabolismo , Espectroscopia de Ressonância Magnética , Oxirredução , Estresse Oxidativo , Conformação Proteica
19.
Eur J Med Chem ; 142: 424-458, 2017 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-28911822

RESUMO

There are around 20 Cyclin-dependent kinases (CDKs) known till date, and various research groups have reported their role in different types of cancer. The X-ray structures of some CDKs especially CDK2 was exploited in the past few years, and several inhibitors have been found, e.g., flavopiridol, indirubicin, roscovitine, etc., but due to the specificity issues of these inhibitors (binding to all CDKs), these were called as pan inhibitors. The revolutionary outcome of palbociclib in 2015 as CDK4/6 inhibitor added a new charm to the specific inhibitor design for CDKs. Computer-aided drug design (CADD) tools added a benefit to the design and development of new CDK inhibitors by studying the binding pattern of the inhibitors to the ATP binding domain of CDKs. Herein, we have attempted a comparative analysis of structural differences between several CDKs ATP binding sites and their inhibitor specificity by depicting the important ligand-receptor interactions for a particular CDK to be targeted. This perspective provides futuristic implications in the design of inhibitors considering the spatial features and structural insights of the specific CDK.


Assuntos
Quinases Ciclina-Dependentes/antagonistas & inibidores , Quinases Ciclina-Dependentes/química , Desenho de Fármacos , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/farmacologia , Sequência de Aminoácidos , Animais , Desenho Assistido por Computador , Cristalografia por Raios X , Quinases Ciclina-Dependentes/metabolismo , Humanos , Modelos Moleculares , Neoplasias/tratamento farmacológico , Conformação Proteica , Alinhamento de Sequência
20.
PLoS One ; 12(7): e0181748, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28759605

RESUMO

THPdb (http://crdd.osdd.net/raghava/thpdb/) is a manually curated repository of Food and Drug Administration (FDA) approved therapeutic peptides and proteins. The information in THPdb has been compiled from 985 research publications, 70 patents and other resources like DrugBank. The current version of the database holds a total of 852 entries, providing comprehensive information on 239 US-FDA approved therapeutic peptides and proteins and their 380 drug variants. The information on each peptide and protein includes their sequences, chemical properties, composition, disease area, mode of activity, physical appearance, category or pharmacological class, pharmacodynamics, route of administration, toxicity, target of activity, etc. In addition, we have annotated the structure of most of the protein and peptides. A number of user-friendly tools have been integrated to facilitate easy browsing and data analysis. To assist scientific community, a web interface and mobile App have also been developed.


Assuntos
Bases de Dados de Proteínas , Peptídeos/uso terapêutico , Proteínas/uso terapêutico , Internet , Aplicativos Móveis , Peptídeos/química , Linguagens de Programação , Proteínas/química , Software , Estados Unidos , United States Food and Drug Administration , Interface Usuário-Computador
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