Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 114
Filtrar
Mais filtros










Base de dados
Intervalo de ano de publicação
1.
J Chem Inf Model ; 61(9): 4131-4138, 2021 09 27.
Artigo em Inglês | MEDLINE | ID: mdl-34519200

RESUMO

Relative binding free energy calculations in drug design are becoming a useful tool in facilitating lead binding affinity optimization in a cost- and time-efficient manner. However, they have been limited by technical challenges such as the manual creation of large numbers of input files to set up, run, and analyze free energy simulations. In this Application Note, we describe FEPrepare, a novel web-based tool, which automates the setup procedure for relative binding FEP calculations for the dual-topology scheme of NAMD, one of the major MD engines, using OPLS-AA force field topology and parameter files. FEPrepare provides the user with all necessary files needed to run a FEP/MD simulation with NAMD. FEPrepare can be accessed and used at https://feprepare.vi-seem.eu/.


Assuntos
Internet , Simulação de Dinâmica Molecular , Entropia , Fenômenos Físicos , Termodinâmica
2.
J Enzyme Inhib Med Chem ; 36(1): 1874-1883, 2021 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-34340614

RESUMO

A library of variously decorated N-phenyl secondary sulphonamides featuring the bicyclic tetrahydroquinazole scaffold was synthesised and biologically evaluated for their inhibitory activity against human carbonic anhydrase (hCA) I, II, IV, and IX. Of note, several compounds were identified showing submicromolar potency and excellent selectivity for the tumour-related hCA IX isoform. Structure-activity relationship data attained for various substitutions were rationalised by molecular modelling studies in terms of both inhibitory activity and selectivity.


Assuntos
Inibidores da Anidrase Carbônica/farmacologia , Biologia Computacional/métodos , Isoenzimas/antagonistas & inibidores , Quinazolinas/química , Sulfonamidas/farmacologia , Espectroscopia de Ressonância Magnética Nuclear de Carbono-13 , Inibidores da Anidrase Carbônica/síntese química , Inibidores da Anidrase Carbônica/química , Avaliação Pré-Clínica de Medicamentos , Simulação de Acoplamento Molecular , Espectroscopia de Prótons por Ressonância Magnética , Relação Estrutura-Atividade , Sulfonamidas/química
3.
J Enzyme Inhib Med Chem ; 36(1): 1783-1797, 2021 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-34340630

RESUMO

Carbonic Anhydrase Activators (CAAs) could represent a novel approach for the treatment of Alzheimer's disease, ageing, and other conditions that require remedial achievement of spatial learning and memory therapy. Within a research project aimed at developing novel CAAs selective for certain isoforms, three series of indole-based derivatives were investigated. Enzyme activation assay on human CA I, II, VA, and VII isoforms revealed several effective micromolar activators, with promising selectivity profiles towards the brain-associated cytosolic isoform hCA VII. Molecular modelling studies suggested a theoretical model of the complex between hCA VII and the new activators and provide a possible explanation for their modulating as well as selectivity properties. Preliminary biological evaluations demonstrated that one of the most potent CAA 7 is not cytotoxic and is able to increase the release of the brain-derived neurotrophic factor (BDNF) from human microglial cells, highlighting its possible application in the treatment of CNS-related disorders.


Assuntos
Anidrases Carbônicas/efeitos dos fármacos , Ativadores de Enzimas/farmacologia , Indóis/farmacologia , Isoenzimas/efeitos dos fármacos , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Espectroscopia de Ressonância Magnética Nuclear de Carbono-13 , Anidrases Carbônicas/metabolismo , Sobrevivência Celular/efeitos dos fármacos , Ativação Enzimática , Ativadores de Enzimas/química , Ensaio de Imunoadsorção Enzimática/métodos , Humanos , Indóis/química , Isoenzimas/metabolismo , Microglia/citologia , Microglia/efeitos dos fármacos , Modelos Moleculares , Espectroscopia de Prótons por Ressonância Magnética , Especificidade por Substrato
4.
J Chem Inf Model ; 61(8): 3835-3845, 2021 08 23.
Artigo em Inglês | MEDLINE | ID: mdl-34270903

RESUMO

Artificial intelligence (AI) algorithms are dramatically redefining the current drug discovery landscape by boosting the efficiency of its various steps. Still, their implementation often requires a certain level of expertise in AI paradigms and coding. This often prevents the use of these powerful methodologies by non-expert users involved in the design of new biologically active compounds. Here, the random matrix discriminant (RMD) algorithm, a high-performance AI method specifically tailored for the identification of new ligands, was implemented in a new fully automated tool, PyRMD. This ligand-based virtual screening tool can be trained using target bioactivity data directly downloaded from the ChEMBL repository without manual intervention. The software automatically splits the available training compounds into active and inactive sets and learns the distinctive chemical features responsible for the compounds' activity/inactivity. PyRMD was designed to easily screen millions of compounds in hours through an automated workflow and intuitive input files, allowing fine tuning of each parameter of the calculation. Additionally, PyRMD features a wealth of benchmark metrics, to accurately probe the model performance, which were used here to gauge its predictive potential and limitations. PyRMD is freely available on GitHub (https://github.com/cosconatilab/PyRMD) as an open-source tool.


Assuntos
Inteligência Artificial , Software , Algoritmos , Descoberta de Drogas , Ligantes
5.
J Med Chem ; 64(12): 8579-8598, 2021 06 24.
Artigo em Inglês | MEDLINE | ID: mdl-34106711

RESUMO

Novel anti-HIV agents are still needed to overcome resistance issues, in particular inhibitors acting against novel viral targets. The ribonuclease H (RNase H) function of the reverse transcriptase (RT) represents a validated and promising target, and no inhibitor has reached the clinical pipeline yet. Here, we present rationally designed non-diketo acid selective RNase H inhibitors (RHIs) based on the quinolinone scaffold starting from former dual integrase (IN)/RNase H quinolinonyl diketo acids. Several derivatives were synthesized and tested against RNase H and viral replication and found active at micromolar concentrations. Docking studies within the RNase H catalytic site, coupled with site-directed mutagenesis, and Mg2+ titration experiments demonstrated that our compounds coordinate the Mg2+ cofactor and interact with amino acids of the RNase H domain that are highly conserved among naïve and treatment-experienced patients. In general, the new inhibitors influenced also the polymerase activity of RT but were selective against RNase H vs the IN enzyme.


Assuntos
Fármacos Anti-HIV/farmacologia , HIV-1/enzimologia , Quinolonas/farmacologia , Inibidores da Transcriptase Reversa/farmacologia , Ribonuclease H do Vírus da Imunodeficiência Humana/antagonistas & inibidores , Fármacos Anti-HIV/síntese química , Fármacos Anti-HIV/metabolismo , Células HeLa , Humanos , Magnésio/metabolismo , Testes de Sensibilidade Microbiana , Simulação de Acoplamento Molecular , Mutagênese Sítio-Dirigida , Mutação , Ligação Proteica , Quinolonas/síntese química , Quinolonas/metabolismo , Inibidores da Transcriptase Reversa/síntese química , Inibidores da Transcriptase Reversa/metabolismo , Ribonuclease H do Vírus da Imunodeficiência Humana/genética , Ribonuclease H do Vírus da Imunodeficiência Humana/metabolismo , Replicação Viral/efeitos dos fármacos
6.
Eur J Med Chem ; 220: 113490, 2021 Aug 05.
Artigo em Inglês | MEDLINE | ID: mdl-33975138

RESUMO

Carbonic Anhydrases (CAs) are pharmaceutically relevant targets for the treatment of several disease conditions. The ubiquitous localization of these enzymes and the high homology shared by the different isoforms represent substantial impediments for the discovery of potential drugs devoid of off-target side effects. As a consequence, substantial efforts are still needed to allow for the full realization of the pharmacological potential of CA modulators. In this contribution, starting from our previous studies, we describe the synthesis of a set of new bicyclic tetrahydroindazoles featuring a secondary sulfonamide. Biological evaluation of the inhibitory activity against the hCA I, II, IV, and IX isoforms allowed drawing a structure-activity relationship profile that was rationalized through theoretical studies. This allowed dissecting the new molecules into the single portions influencing the zinc chelation properties and the selectivity profile thereby offering a new platform for the discovery of new isotype selective CA inhibitors.


Assuntos
Compostos Bicíclicos Heterocíclicos com Pontes/farmacologia , Inibidores da Anidrase Carbônica/farmacologia , Anidrases Carbônicas/metabolismo , Indazóis/farmacologia , Sulfonamidas/farmacologia , Compostos Bicíclicos Heterocíclicos com Pontes/química , Inibidores da Anidrase Carbônica/síntese química , Inibidores da Anidrase Carbônica/química , Relação Dose-Resposta a Droga , Humanos , Indazóis/química , Isoenzimas/antagonistas & inibidores , Isoenzimas/metabolismo , Modelos Moleculares , Estrutura Molecular , Relação Estrutura-Atividade , Sulfonamidas/síntese química , Sulfonamidas/química
7.
J Chem Inf Model ; 61(4): 2062-2073, 2021 04 26.
Artigo em Inglês | MEDLINE | ID: mdl-33784094

RESUMO

During almost all 2020, coronavirus disease 2019 (COVID-19) pandemic has constituted the major risk for the worldwide health and economy, propelling unprecedented efforts to discover drugs for its prevention and cure. At the end of the year, these efforts have culminated with the approval of vaccines by the American Food and Drug Administration (FDA) and the European Medicines Agency (EMA) giving new hope for the future. On the other hand, clinical data underscore the urgent need for effective drugs to treat COVID-19 patients. In this work, we embarked on a virtual screening campaign against the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Mpro chymotrypsin-like cysteine protease employing our in-house database of peptide and non-peptide ligands characterized by different types of warheads acting as Michael acceptors. To this end, we employed the AutoDock4 docking software customized to predict the formation of a covalent adduct with the target protein. In vitro verification of the inhibition properties of the most promising candidates allowed us to identify two new lead inhibitors that will deserve further optimization. From the computational point of view, this work demonstrates the predictive power of AutoDock4 and suggests its application for the in silico screening of large chemical libraries of potential covalent binders against the SARS-CoV-2 Mpro enzyme.


Assuntos
COVID-19 , Inibidores de Proteases , Antivirais/farmacologia , Humanos , Simulação de Acoplamento Molecular , Pandemias , Inibidores de Proteases/farmacologia , SARS-CoV-2
8.
J Med Chem ; 64(7): 4089-4108, 2021 04 08.
Artigo em Inglês | MEDLINE | ID: mdl-33733768

RESUMO

Neuropeptide S modulates important neurobiological functions including locomotion, anxiety, and drug abuse through interaction with its G protein-coupled receptor known as neuropeptide S receptor (NPSR). NPSR antagonists are potentially useful for the treatment of substance abuse disorders against which there is an urgent need for new effective therapeutic approaches. Potent NPSR antagonists in vitro have been discovered which, however, require further optimization of their in vivo pharmacological profile. This work describes a new series of NPSR antagonists of the oxazolo[3,4-a]pyrazine class. The guanidine derivative 16 exhibited nanomolar activity in vitro and 5-fold improved potency in vivo compared to SHA-68, a reference pharmacological tool in this field. Compound 16 can be considered a new tool for research studies on the translational potential of the NPSergic system. An in-depth molecular modeling investigation was also performed to gain new insights into the observed structure-activity relationships and provide an updated model of ligand/NPSR interactions.


Assuntos
Oxazóis/farmacologia , Pirazinas/farmacologia , Receptores Acoplados a Proteínas G/antagonistas & inibidores , Receptores de Neuropeptídeos/antagonistas & inibidores , Animais , Células HEK293 , Humanos , Locomoção/efeitos dos fármacos , Camundongos Knockout , Simulação de Acoplamento Molecular , Estrutura Molecular , Oxazóis/síntese química , Oxazóis/metabolismo , Ligação Proteica , Pirazinas/síntese química , Pirazinas/metabolismo , Receptores Acoplados a Proteínas G/metabolismo , Receptores de Neuropeptídeos/metabolismo , Relação Estrutura-Atividade
9.
Antioxidants (Basel) ; 9(9)2020 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-32882797

RESUMO

Oxidative stress (OS) arising from tissue redox imbalance, critically contributes to the development of neurodegenerative disorders. Thus, natural compounds, owing to their antioxidant properties, have promising therapeutic potential. Pres phytum (PRES) is a nutraceutical product composed of leaves- and flowers-extracts of Olea europaea L. and Hibiscus sabdariffa L., respectively, the composition of which has been characterized by HPLC coupled to a UV-Vis and QqQ-Ms detector. As PRES possess antioxidant, antiapoptotic and anti-inflammatory properties, the aim of this study was to assess its neuroprotective effects in human neuroblastoma SH-SY5Y cells and in rat brain slices subjected to OS. PRES (1-50 µg/mL) reverted the decrease in viability as well as the increase in sub-diploid-, DAPI-and annexin V-positive-cells, reduced ROS formation, recovered the mitochondrial potential and caspase-3 and 9 activity changes caused by OS. PRES (50-100 µg/mL) neuroprotective effects occurred also in rat brain slices subjected to H2O2 challenge. Finally, as the neuroprotective potential of PRES is strictly related to its penetration into the brain and a relatively good pharmacokinetic profile, an in-silico prediction of its components drug-like properties was carried out. The present results suggest the possibility of PRES as a nutraceutical, which could help in preventing neurodegenerative diseases.

10.
Chemistry ; 26(44): 10113-10125, 2020 Aug 06.
Artigo em Inglês | MEDLINE | ID: mdl-32603023

RESUMO

Here we investigated the structural and biological effects ensuing from the disulfide bond replacement of a potent and selective C-X-C chemokine receptor type 4 (CXCR4) peptide antagonist, with 1,4- and 1,5- disubstituted 1,2,3-triazole moieties. Both strategies produced candidates that showed high affinity and selectivity against CXCR4. Notably, when assessed for their ability to modulate the CXCL12-mediated cell migration, the 1,4-triazole variant conserved the antagonistic effect in the low-mid nanomolar range, while the 1,5-triazole one displayed the ability to activate the migration, becoming the first in class low-molecular-weight CXCR4 peptide agonist. By combining NMR and computational studies, we provided a valuable model that highlighted differences in the interactions of the two peptidomimetics with the receptor that could account for their different functional profile. Finally, we envisage that our findings could be translated to different GPCR-interacting peptides for the pursuit of novel chemical probes that could assist in dissecting the complex puzzle of this fundamental class of transmembrane receptors.


Assuntos
Dissulfetos/química , Peptídeos/química , Peptídeos/farmacologia , Receptores CXCR4/química , Triazóis/química , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Quimiocina CXCL12/farmacologia , Humanos , Ligantes , Peptidomiméticos , Receptores CXCR4/agonistas
11.
ChemMedChem ; 15(16): 1552-1561, 2020 08 19.
Artigo em Inglês | MEDLINE | ID: mdl-32567172

RESUMO

In this paper, we report the design, synthesis and biological investigation of a series of peptidyl vinyl ketones obtained by modifying the P2 fragment of previously reported highly potent inhibitors of rhodesain, the main cysteine protease of Trypanosoma brucei rhodesiense. Investigation of the structure-activity relationship led us to identify new rhodesain inhibitors endowed with an improved selectivity profile (a selectivity index of up to 22 000 towards the target enzyme), and/or an improved antitrypanosomal activity in the sub-micromolar range.


Assuntos
Cisteína Endopeptidases/metabolismo , Inibidores de Cisteína Proteinase/farmacologia , Cetonas/farmacologia , Peptídeos/farmacologia , Tripanossomicidas/farmacologia , Trypanosoma brucei brucei/efeitos dos fármacos , Inibidores de Cisteína Proteinase/síntese química , Inibidores de Cisteína Proteinase/química , Relação Dose-Resposta a Droga , Cetonas/síntese química , Cetonas/química , Estrutura Molecular , Testes de Sensibilidade Parasitária , Peptídeos/síntese química , Peptídeos/química , Relação Estrutura-Atividade , Tripanossomicidas/síntese química , Tripanossomicidas/química , Trypanosoma brucei brucei/metabolismo
12.
ACS Med Chem Lett ; 11(5): 798-805, 2020 May 14.
Artigo em Inglês | MEDLINE | ID: mdl-32435387

RESUMO

Due to the biological liability of diketo acid (DKA) chain, we transferred this element of our previously reported anti-HIV-1 pyrrolyl derivatives to a non-DKA scaffold, obtaining a series of pyrrolyl-pyrazole carboxylic acids as new RNase H inhibitors. Among the newly synthesized derivatives, oxyphenylpyrrolyl-pyrazoles demonstrated inhibitory activities within the low micromolar/submicromolar range with compound 11b being the most potent. Interestingly, all tested compounds showed up to 2 orders of magnitude of selectivity for RNase H vs integrase. Docking studies within the RNase H catalytic site, coupled with site-directed mutagenesis, showed the key structural features that could confer the ability to establish specific interactions within RNase H. Furthermore, they proved the ability of our compounds to interact with amino acids highly conserved among HIV-1 subspecies isolated among patients carrying drug-resistant variants. In the end, the newly discovered pyrazole carboxylic acid derivatives feature promising serum stability with respect to their corresponding DKAs.

13.
ChemMedChem ; 15(11): 995-1001, 2020 06 04.
Artigo em Inglês | MEDLINE | ID: mdl-32329206

RESUMO

Starting from the reversible rhodesain inhibitors 1 a-c, which have Ki values towards the target protease in the low-micromolar range, we have designed a series of peptidomimetics, 2 a-g, that contain a benzodiazepine scaffold as a ß-turn mimetic; they are characterized by a specific peptide sequence for the inhibition of rhodesain. Considering that irreversible inhibition is strongly desirable in the case of a parasitic target, a vinyl ester moiety acting as Michael-acceptor was introduced as the warhead; this portion was functionalized in order to evaluate the size of corresponding enzyme pocket that could accommodate this substituent. With this investigation, we identified an irreversible rhodesain inhibitor (i. e., 2 g) with a k2nd value of 90 000 M-1 min-1 that showed antitrypanosomal activity in the low-micromolar range (EC50 =1.25 µM), this may be considered a promising lead compound in the drug-discovery process for treating human African trypanosomiasis (HAT).


Assuntos
Antiprotozoários/farmacologia , Benzodiazepinas/farmacologia , Cisteína Endopeptidases/metabolismo , Inibidores de Cisteína Proteinase/farmacologia , Desenvolvimento de Medicamentos , Peptidomiméticos/farmacologia , Trypanosoma brucei rhodesiense/efeitos dos fármacos , Antiprotozoários/síntese química , Antiprotozoários/química , Benzodiazepinas/síntese química , Benzodiazepinas/química , Inibidores de Cisteína Proteinase/síntese química , Inibidores de Cisteína Proteinase/química , Relação Dose-Resposta a Droga , Estrutura Molecular , Testes de Sensibilidade Parasitária , Peptidomiméticos/síntese química , Peptidomiméticos/química , Relação Estrutura-Atividade , Trypanosoma brucei rhodesiense/enzimologia
14.
Epigenetics ; 15(6-7): 664-683, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31942817

RESUMO

SIRT1, a NAD+-dependent deacetylase, is the most well-studied member of class III histone deacetylases. Due to its wide range of activities and substrate targets, this enzyme has emerged as a major regulator of different physiological processes. However, SIRT1-mediated alterations are also implicated in the pathogenesis of several conditions, including metabolic and neurodegenerative disorders, and cancer. Current evidence highlights the potential role of SIRT1 as an attractive therapeutic target for disease prevention and treatment strategies, thus propelling the development of new pharmacological agents. By high-throughput screening of a large library of compounds, we identified SCIC2 as an effective SIRT1 activator. This small molecule showed enzymatic activity of 135.8% at 10 µM, an AC50 value of 50 ± 1.8 µM, and bound SIRT1 with a KD of 26.4 ± 0.6 µM. In order to potentiate its SIRT1-activating ability, SCIC2 was subjected to modelling studies, leading to the identification of a more potent derivative, SCIC2.1. SCIC2.1 displayed higher SIRT1 activity (175%; AC50 = 36.83 ± 2.23 µM), stronger binding to SIRT1, and greater cell permeability than SCIC2. At cellular level, both molecules did not alter the cell cycle progression of cancer cells and normal cells, and were able to strengthen SIRT1-mediated effects in stress response. Finally, SCIC2 and SCIC2.1 attenuated induction of senescence by reducing senescence-associated ß-galactosidase activity. Our findings warrant further investigation of these two novel SIRT1 activators in in vivo and human studies.


Assuntos
Senescência Celular , Inibidores de Histona Desacetilases/farmacologia , Sirtuína 1/antagonistas & inibidores , Bibliotecas de Moléculas Pequenas/farmacologia , Estresse Fisiológico , Animais , Sítios de Ligação , Células CACO-2 , Epigênese Genética , Células Hep G2 , Inibidores de Histona Desacetilases/química , Humanos , Simulação de Acoplamento Molecular , Ligação Proteica , Ratos , Sirtuína 1/química , Sirtuína 1/metabolismo , Bibliotecas de Moléculas Pequenas/química
15.
Antiviral Res ; 174: 104671, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31812637

RESUMO

The management of Human Immunodeficiency Virus type 1 (HIV-1) infection requires life-long treatment that is associated with chronic toxicity and possible selection of drug-resistant strains. A new opportunity for drug intervention is offered by antivirals that act as allosteric inhibitors targeting two viral functions (dual inhibitors). In this work, we investigated the effects of 5,6-dihydroxyindole-2-carboxylic acid (DHICA) derivatives on both HIV-1 Integrase (IN) and Reverse Transcriptase associated Ribonuclease H (RNase H) activities. Among the tested compounds, the dihydroxyindole-carboxamide 5 was able to inhibit in the low micromolar range (1-18 µM) multiple functions of IN, including functional IN-IN interactions, IN-LEDGF/p75 binding and IN catalytic activity. Docking and site-directed mutagenesis studies have suggested that compound 5 binds to a previously described HIV-1 IN allosteric pocket. These observations indicate that 5 is structurally and mechanistically distinct from the published allosteric HIV-1 IN inhibitors. Moreover, compound 5 also inhibited HIV-1 RNase H function, classifying this molecule as a dual HIV-1 IN and RNase H inhibitor able to impair the HIV-1 virus replication in cell culture. Overall, we identified a new scaffold as a suitable platform for the development of novel dual HIV-1 inhibitors.


Assuntos
Ácidos Carboxílicos/farmacologia , Inibidores de Integrase de HIV/farmacologia , Transcriptase Reversa do HIV/antagonistas & inibidores , HIV-1/efeitos dos fármacos , Ribonuclease H do Vírus da Imunodeficiência Humana/antagonistas & inibidores , Ácidos Carboxílicos/química , Linhagem Celular , Descoberta de Drogas , Infecções por HIV/virologia , Integrase de HIV/metabolismo , Inibidores de Integrase de HIV/química , Humanos , Simulação de Acoplamento Molecular , Estrutura Molecular , Relação Estrutura-Atividade
16.
J Med Chem ; 62(23): 10617-10629, 2019 12 12.
Artigo em Inglês | MEDLINE | ID: mdl-31714776

RESUMO

This paper describes an optimization strategy of the highly active vinyl ketone 3 which was recognized as a strong inhibitor of rhodesain of Trypanosoma brucei rhodesiense, endowed with a ksecond value of 67 × 106 M-1 min-1 coupled with a high binding affinity (Ki = 38 pM). We now report a new structure-activity relationship study based on structural variations on the P3, P2, and P1' sites which led us to identify two potent lead compounds, i.e., vinyl ketones 4h and 4k. Vinyl ketone 4h showed an impressive potency toward rhodesain (ksecond = 8811 × 105) coupled to a good antiparasitic activity (EC50 = 3.6 µM), while vinyl ketone 4k proved to possess the highest binding affinity toward the trypanosomal protease (Ki = 0.6 pM) and a submicromolar antiparasitic activity (EC50 = 0.67 µM), thus representing new lead compounds in the drug discovery process for the treatment of Human African Trypanosomiasis.


Assuntos
Cisteína Endopeptidases/metabolismo , Tripanossomicidas/química , Tripanossomicidas/farmacologia , Trypanosoma brucei rhodesiense/efeitos dos fármacos , Tripanossomíase Africana/tratamento farmacológico , Humanos , Estrutura Molecular , Conformação Proteica , Relação Estrutura-Atividade , Sulfonas/química , Sulfonas/farmacologia , Trypanosoma brucei rhodesiense/metabolismo
17.
J Enzyme Inhib Med Chem ; 34(1): 1697-1710, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31537132

RESUMO

Inhibition of Carbonic Anhydrases (CAs) has been clinically exploited for many decades for a variety of therapeutic applications. Within a research project aimed at developing novel classes of CA inhibitors (CAIs) with a proper selectivity for certain isoforms, a series of derivatives featuring the 2-substituted-benzimidazole-6-sulfonamide scaffold, conceived as frozen analogs of Schiff bases and secondary amines previously reported in the literature as CAIs, were investigated. Enzyme inhibition assays on physiologically relevant human CA I, II, IX and XII isoforms revealed a number of potent CAIs, showing promising selectivity profiles towards the transmembrane tumor-associated CA IX and XII enzymes. Computational studies were attained to clarify the structural determinants behind the activities and selectivity profiles of the novel inhibitors.


Assuntos
Benzimidazóis/química , Inibidores da Anidrase Carbônica/síntese química , Sulfonamidas/síntese química , Aminas/química , Anidrase Carbônica I/antagonistas & inibidores , Anidrase Carbônica II/antagonistas & inibidores , Inibidores da Anidrase Carbônica/química , Inibidores da Anidrase Carbônica/farmacologia , Anidrases Carbônicas/química , Humanos , Isoenzimas/metabolismo , Simulação de Acoplamento Molecular , Estrutura Molecular , Proteínas do Tecido Nervoso/antagonistas & inibidores , Bases de Schiff/química , Relação Estrutura-Atividade , Sulfonamidas/química , Sulfonamidas/farmacologia
18.
ACS Chem Neurosci ; 10(8): 3805-3814, 2019 08 21.
Artigo em Inglês | MEDLINE | ID: mdl-31268683

RESUMO

Translocator protein 18 kDa (TSPO) is a validated pharmacological target for the development of new treatments for neurological disorders. N,N-Dialkyl-2-phenylindol-3-ylglyoxylamides (PIGAs) are effective TSPO modulators and potentially useful therapeutics for the treatment of anxiety, central nervous system pathologies featuring astrocyte loss, and inflammatory-based neuropathologies. For this class of compounds, no correlation exists between the TSPO binding affinity and the corresponding functional efficacy. Rather, their biological effectiveness correlates with the kinetics of the unbinding events and more specifically with the residence time (RT). So far, the structural reasons for the different recorded RT of congeneric PIGAs remain elusive. Here, to understand the different kinetics of PIGAs, their unbinding paths were studied by employing enhanced-sampling molecular dynamics simulations. Results of these studies revealed how subtle structural differences between PIGAs have a substantial effect on the unbinding energetics. In particular, during the egress from the TSPO binding site, slow-dissociating PIGAs find tight interactions with the protein LP1 region thereby determining a long RT. Further support to these findings was achieved by in vivo studies, which demonstrated how the anxiolytic effect observed for the inspected PIGAs correlated with their RT to TSPO.


Assuntos
Proteínas de Transporte/metabolismo , Receptores de GABA-A/metabolismo , Animais , Ansiolíticos/farmacologia , Sítios de Ligação , Simulação por Computador , Masculino , Simulação de Dinâmica Molecular , Ligação Proteica , Ratos , Ratos Sprague-Dawley
19.
Org Lett ; 21(16): 6378-6382, 2019 08 16.
Artigo em Inglês | MEDLINE | ID: mdl-31361506

RESUMO

We investigated the ultrasonication-mediated effects on the Fmoc-based solid-phase peptide synthesis (SPPS). Our study culminated with the development of an ultrasound-assisted strategy (US-SPPS) that allowed for the synthesis of different biologically active peptides (up to 44-mer), with a remarkable savings of material and reaction time. Noteworthy, ultrasonic irradiation did not exacerbate the main side reactions and improved the synthesis of peptides endowed with "difficult sequences", placing the US-SPPS among the current high-efficient peptide synthetic strategies.

20.
J Enzyme Inhib Med Chem ; 34(1): 1152-1157, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31179771

RESUMO

Nine indole derivatives (9a-i) were tested as potential inhibitors of the Keap1-Nrf2 interaction. This class of compounds increases the intracellular levels of the transcription factor Nrf2 and the consequent expression of enzymes encoded by genes containing the antioxidant response element (ARE). In the ARE-luciferase reporter assay only 9e-g revealed to be remarkably more active than t-butylhydroxyquinone (t-BHQ), with 9g standing out as the best performing compound. While 9e and 9f are weak acids, 9g is an ampholyte prevailing as a zwitterion in neutral aqueous solutions. The ability of 9e-g to significantly increase levels of Nrf2, NADPH:quinone oxidoreductase 1, and transketolase (TKT) gave further support to the hypothesis that these compounds act as inhibitors of the Keap1-Nrf2 interaction. Docking simulations allowed us to elucidate the nature of the putative interactions between 9g and Keap1.


Assuntos
Indóis/química , Indóis/farmacologia , Proteína 1 Associada a ECH Semelhante a Kelch/metabolismo , Fator 2 Relacionado a NF-E2/metabolismo , Relação Dose-Resposta a Droga , Células HeLa , Humanos , Modelos Moleculares , Estrutura Molecular , Ligação Proteica/efeitos dos fármacos , Relação Estrutura-Atividade
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...