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1.
J Inorg Biochem ; 246: 112289, 2023 09.
Artigo em Inglês | MEDLINE | ID: mdl-37354606

RESUMO

High energy consumption in the nervous system requires a continuous supply of O2. This role is assisted by proteins from the globin super-family in the nerve cells of invertebrates, where 'nerve hemoglobins' (nHbs) are mainly present at mM concentrations and exhibit oxygen affinities comparable to those of vertebrate myoglobins. To gain insight into the structural bases of this function, we report the crystal structure of nHb from the Atlantic surf clam Spisula solidissima (SsHb), previously suggested to display a bis-histidyl hexa-coordinated heme in the deoxy state, high O2 affinity, and ligand binding cooperativity when assayed in situ. The crystallized protein forms a dimer through packing of a 4-helix bundle involving helices E and F of each subunit. The SsHb 'classic' globin fold displays bis-histidyl (His71(E7) and His103(F8)) hexa-coordination of the heme-Fe atom, with structural and dynamics variations found in the inter-helix hinge regions. Molecular Dynamics simulations of both monomeric and dimeric species in the bis-histidyl hexa-coordinated, deoxy penta-coordinated, and O2-bound hexa-coordinated states reveal distinct structural rearrangements at the interface between subunits in the dimer; these would affect the magnitude of the conformational fluctuations observed between monomer and dimer, and the topology of cavities within the protein matrix and at the interface. These results point to a distal site opening mechanism allowing access of the exogenous ligand to the heme and cast hypotheses on the dimer interface structural and dynamic properties that may support ligand binding cooperativity in dimeric SsHb.


Assuntos
Spisula , Animais , Spisula/metabolismo , Ligantes , Hemoglobinas/química , Heme/química , Mioglobina , Oxigênio/metabolismo
2.
Pharmaceutics ; 14(11)2022 Oct 30.
Artigo em Inglês | MEDLINE | ID: mdl-36365159

RESUMO

One of the pathological hallmarks of Alzheimer's disease (AD) is the formation of amyloid-ß plaques. Since acetylcholinesterase (AChE) promotes the formation of such plaques, the inhibition of this enzyme could slow down the progression of amyloid-ß aggregation, hence being complementary to the palliative treatment of cholinergic decline. Antiaggregation assays performed for apigenin and quercetin, which are polyphenolic compounds that exhibit inhibitory properties against the formation of amyloid plaques, reveal distinct inhibitory effects of these compounds on Aß40 aggregation in the presence and absence of AChE. Furthermore, the analysis of the amyloid fibers formed in the presence of these flavonoids suggests that the Aß40 aggregates present different quaternary structures, viz., smaller molecular assemblies are generated. In agreement with a noncompetitive inhibition of AChE, molecular modeling studies indicate that these effects may be due to the binding of apigenin and quercetin at the peripheral binding site of AChE. Since apigenin and quercetin can also reduce the generation of reactive oxygen species, the data achieved suggest that multitarget catechol-type compounds may be used for the simultaneous treatment of various biological hallmarks of AD.

3.
Sci Rep ; 12(1): 4225, 2022 03 10.
Artigo em Inglês | MEDLINE | ID: mdl-35273216

RESUMO

Endothelial adenosine monophosphate-activated protein kinase (AMPK) plays a critical role in the regulation of vascular tone through stimulating nitric oxide (NO) release in endothelial cells. Since obesity leads to endothelial dysfunction and AMPK dysregulation, AMPK activation might be an important strategy to restore vascular function in cardiometabolic alterations. Here, we report the identification of a novel AMPK modulator, the indolic derivative IND6, which shows affinity for AMPKα1ß1γ1, the primary AMPK isoform in human EA.Hy926 endothelial cells. IND6 shows inhibitory action of the enzymatic activity in vitro, but increases the levels of p-Thr174AMPK, p-Ser1177eNOS and p-Ser79ACC in EA.Hy926. This paradoxical finding might be explained by the ability of IND6 to act as a mixed-type inhibitor, but also to promote the enzyme activation by adopting two distinct binding modes at the ADaM site. Moreover, functional assays reveal that IND6 increased the eNOS-dependent production of NO and elicited a concentration-dependent vasodilation of endothelium-intact rat aorta due to AMPK and eNOS activation, demonstrating a functional activation of the AMPK-eNOS-NO endothelial pathway. This kinase inhibition profile, combined with the paradoxical AMPK activation in cells and arteries, suggests that these new chemical entities may constitute a valuable starting point for the development of new AMPK modulators with therapeutic potential for the treatment of vascular complications associated with obesity.


Assuntos
Proteínas Quinases Ativadas por AMP , Vasodilatação , Proteínas Quinases Ativadas por AMP/metabolismo , Animais , Células Endoteliais/metabolismo , Endotélio Vascular/metabolismo , Humanos , Óxido Nítrico/metabolismo , Óxido Nítrico Sintase Tipo III/metabolismo , Obesidade/metabolismo , Fosforilação , Ratos , Transdução de Sinais , Vasodilatação/efeitos dos fármacos
4.
Pharmaceuticals (Basel) ; 14(3)2021 Mar 04.
Artigo em Inglês | MEDLINE | ID: mdl-33806467

RESUMO

The interaction between drugs and transport proteins, such as albumins, is a key factor in drug bioavailability. One of the techniques commonly used for the evaluation of the drug-protein complex formation is fluorescence. This work studies the interaction of human serum albumin (HSA) with four non-steroidal anti-inflammatory drugs (NSAIDs)-ibuprofen, flurbiprofen, naproxen, and diflunisal-by monitoring the fluorescence quenching when the drug-albumin complex is formed. Two approaches-the double logarithm Stern-Volmer equation and the STAR program-are used to evaluate the binding parameters. The results are analyzed considering the binding properties, determined by using other complementary techniques and the available structural information of albumin complexes with NSAID-related compounds. Finally, this combined analysis has been synergistically used to interpret the binding of flurbiprofen to HSA.

5.
ChemMedChem ; 16(1): 105-107, 2021 01 08.
Artigo em Inglês | MEDLINE | ID: mdl-33428329

RESUMO

Here we highlight a sound and unique work reported by Chen and co-workers entitled "HIV-1 fusion inhibitors targeting the membrane-proximal external region of Env spikes" (Xiao et al., Nat. Chem. Biol. 2020, 16, 529). In this article, the authors identify, by means of a clever antibody-guided strategy, several small molecules as fusion inhibitors of HIV-1 replication acting at the membrane proximal external region (MPER) of the HIV-1 envelope (Env) spike. MPER, which was previously recognized as a vaccine target, emerges as a novel druggable target for the discovery of HIV-1 fusion inhibitors. The compounds (exemplified by dequalinium and dequalinium-inspired analogues) prevent the conformational changes of Env from the prefusion species to the intermediate states required for membrane fusion. This work not only paves the way to novel, specific and useful anti-HIV-1 inhibitors, but also discloses new therapeutic strategies against other infectious diseases.


Assuntos
Inibidores da Fusão de HIV/química , HIV-1/metabolismo , Produtos do Gene env do Vírus da Imunodeficiência Humana/química , Anticorpos Neutralizantes/química , Anticorpos Neutralizantes/imunologia , Sítios de Ligação , Dequalínio/análogos & derivados , Dequalínio/metabolismo , Dequalínio/farmacologia , Inibidores da Fusão de HIV/metabolismo , Inibidores da Fusão de HIV/farmacologia , Humanos , Relação Estrutura-Atividade , Internalização do Vírus/efeitos dos fármacos , Produtos do Gene env do Vírus da Imunodeficiência Humana/metabolismo
6.
Rev. biol. trop ; 67(3)jun. 2019.
Artigo em Inglês | LILACS-Express | LILACS | ID: biblio-1507524

RESUMO

Colossoma macropomum is a frugivorous fish from the Amazon and Orinoco river basins. This species has an important economic and social role in both river watersheds; it also has been overfished for more than 40 years, leading to changes in the populations structure. Currently adults are less common in fisheries, while juveniles are more frequently fished and sold in several market places along the Amazon River. Reportedly adult individuals consume a vast quantity of fruits and seeds and has been recognized as effective seed dispersers that plays a significant ecological role. Although frugivorous fishes are important dispersers in tropical rainforests, assessments of their effectiveness in dispersing seeds and in the effect on the germination of these ingested seeds are still insufficient. Cecropia latiloba and Cecropia membranacea are two pioneer tree species that initiate the succession process in the tropical forest and are both widely consumed by C. macropomum. In this study we aimed to verify if the Cecropia seeds that pass through the digestive tract of juveniles of C. macropomum would show improved germination. The results obtained through controlled experiments confirm that seeds that pass through the digestive tract of C. macropomum retained their germination capacity. Although the responses in the improvement of the germination variables (germination capacity, minimum imbibition time, time necessary for reaching 50 % germination capacity, emergence velocity index and germination mean time) did not show statistical differences between treatments, the seedlings that grew from the seeds consumed by the fish were taller than those without the digestive treatment. We conclude that juveniles of C. macropomum have the possibility to disperse the seeds of these Cecropia species.


Colossoma macropomum es un pez frugívoro de las cuencas del Amazonas y el Orinoco. Esta especie tiene un importante papel económico y social en ambas cuencas; sin embargo, ha sido sobreexplotada por más de 40 años, lo que ha llevado a cambios en la estructura de sus poblaciones. Actualmente los adultos son menos comunes en las pesquerías, mientras que los juveniles son atrapados y vendidos en varios mercados a lo largo del río Amazonas con mayor frecuencia. Se ha reportado que los individuos adultos consumen grandes cantidades de frutas y semillas, y han sido reconocidos como dispersores efectivos con un papel ecológico vital. A pesar de que los peces frugívoros son dispersores importantes en los bosques tropicales, los estudios sobre su efectividad en la dispersión de semillas y sobre la capacidad de germinación y la viabilidad de las semillas ingeridas son aún insuficientes. Cecropia latiloba y Cecropia membranacea son dos especies de árboles pioneros que inician el proceso de sucesión en los bosques tropicales; ambas son ampliamente consumidas por C. macropomum. El objetivo de este estudio fue verificar si las semillas de Cecropia que pasaron por el tracto digestivo de los juveniles de C. macropomum mejorarían su germinación. Los resultados obtenidos a través de experimentos controlados confirmaron que las semillas que pasan a través del tracto digestivo de C. macropomum mantienen su capacidad de germinar. Aunque las variables de germinación (capacidad de germinación, tiempo de imbibición mínimo, tiempo necesario para alcanzar el 50 % de la capacidad de germinación, índice de velocidad de emergencia y tiempo medio de germinación) no mostraron diferencias estadísticas entre tratamientos, las plántulas que crecieron de las semillas consumidas por los peces crecieron más que aquellas provenientes de semillas no ingeridas. Concluimos que los juveniles de C. macropomum tienen la posibilidad de dispersar las semillas de estas especies de Cecropia.

7.
J Med Chem ; 62(4): 2083-2098, 2019 02 28.
Artigo em Inglês | MEDLINE | ID: mdl-30721060

RESUMO

Diarylpyrimidine derivatives (DAPYs) exhibit robust anti-HIV-1 potency, although they have been compromised by E138K variant and severe side-effects and been suffering from poor water solubility. In the present work, hydrophilic morpholine or methylsulfonyl and sulfamide-substituted piperazine/piperidines were introduced into the right wing of DAPYs targeting the solvent-exposed tolerant region I. The anti-HIV-1 activities of 11c (EC50(WT) = 0.0035 µM, EC50(E138K) = 0.0075 µM) were the same as and 2-fold better than that of the lead etravirine against the wild-type and E138K mutant HIV-1, respectively, with a relative low cytotoxicity (CC50 ≥ 173 µM). Further test showed a significant improvement in the water solubility of 11c. Besides, 11c displayed no significant inhibition on main cytochrome P450 enzymes and exhibited no acute/subacute toxicities at doses of 2000 mg·kg-1/50 mg·kg-1 in mice. Taken together, we consider that 11c is a promising lead for further structural optimization.


Assuntos
Pirimidinas/farmacologia , Inibidores da Transcriptase Reversa/farmacologia , Animais , Sítios de Ligação , Linhagem Celular Tumoral , Feminino , Transcriptase Reversa do HIV/química , Transcriptase Reversa do HIV/genética , HIV-1/efeitos dos fármacos , Humanos , Masculino , Camundongos , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Estrutura Molecular , Mutação , Pirimidinas/síntese química , Pirimidinas/toxicidade , Inibidores da Transcriptase Reversa/síntese química , Inibidores da Transcriptase Reversa/toxicidade , Solubilidade , Relação Estrutura-Atividade
8.
J Med Chem ; 62(3): 1484-1501, 2019 02 14.
Artigo em Inglês | MEDLINE | ID: mdl-30624934

RESUMO

To address drug resistance to HIV-1 non-nucleoside reverse transcriptase inhibitors (NNRTIs), a series of novel diarylpyrimidine (DAPY) derivatives targeting "tolerant region I" and "tolerant region II" of the NNRTIs binding pocket (NNIBP) were designed utilizing a structure-guided scaffold-hopping strategy. The dihydrofuro[3,4- d]pyrimidine derivatives 13c2 and 13c4 proved to be exceptionally potent against a wide range of HIV-1 strains carrying single NNRTI-resistant mutations (EC50 = 0.9-8.4 nM), which were remarkably superior to that of etravirine (ETV). Meanwhile, both compounds exhibited comparable activities with ETV toward the virus with double mutations F227L+V106A and K103N+Y181C. Furthermore, the most active compound 13c2 showed favorable pharmacokinetic properties with an oral bioavailability of 30.96% and a half-life of 11.1 h, which suggested that 13c2 is worth further investigation as a novel NNRTI to circumvent drug resistance.


Assuntos
Fármacos Anti-HIV/farmacologia , Furanos/farmacologia , HIV-1/enzimologia , Pirimidinas/farmacologia , Inibidores da Transcriptase Reversa/farmacologia , Animais , Fármacos Anti-HIV/síntese química , Fármacos Anti-HIV/farmacocinética , Sítios de Ligação , Linhagem Celular Tumoral , Furanos/síntese química , Furanos/farmacocinética , Transcriptase Reversa do HIV/química , Transcriptase Reversa do HIV/metabolismo , Humanos , Masculino , Testes de Sensibilidade Microbiana , Simulação de Dinâmica Molecular , Estrutura Molecular , Pirimidinas/síntese química , Pirimidinas/farmacocinética , Ratos Wistar , Inibidores da Transcriptase Reversa/síntese química , Inibidores da Transcriptase Reversa/farmacocinética , Relação Estrutura-Atividade
9.
Future Med Chem ; 9(10): 965-981, 2017 06.
Artigo em Inglês | MEDLINE | ID: mdl-28632395

RESUMO

AIM: Simultaneous modulation of several key targets of the pathological network of Alzheimer's disease (AD) is being increasingly pursued as a promising option to fill the critical gap of efficacious drugs against this condition. MATERIALS & METHODS: A short series of compounds purported to hit multiple targets of relevance in AD has been designed, on the basis of their distinct basicities estimated from high-level quantum mechanical computations, synthesized, and subjected to assays of inhibition of cholinesterases, BACE-1, and Aß42 and tau aggregation, of antioxidant activity, and of brain permeation. RESULTS: Using, as a template, a lead rhein-huprine hybrid with an interesting multitarget profile, we have developed second-generation compounds, designed by the modification of the huprine aromatic ring. Replacement by [1,8]-naphthyridine or thieno[3,2-e]pyridine systems resulted in decreased, although still potent, acetylcholinesterase or BACE-1 inhibitory activities, which are more balanced relative to their Aß42 and tau antiaggregating and antioxidant activities. CONCLUSION: Second-generation naphthyridine- and thienopyridine-based rhein-huprine hybrids emerge as interesting brain permeable compounds that hit several crucial pathogenic factors of AD.


Assuntos
Doença de Alzheimer/tratamento farmacológico , Aminoquinolinas/farmacologia , Antraquinonas/farmacologia , Antioxidantes/farmacologia , Inibidores da Colinesterase/farmacologia , Desenho de Fármacos , Compostos Heterocíclicos de 4 ou mais Anéis/farmacologia , Acetilcolinesterase/metabolismo , Doença de Alzheimer/metabolismo , Aminoquinolinas/química , Antraquinonas/química , Antioxidantes/síntese química , Antioxidantes/química , Butirilcolinesterase/metabolismo , Inibidores da Colinesterase/síntese química , Inibidores da Colinesterase/química , Relação Dose-Resposta a Droga , Compostos Heterocíclicos de 4 ou mais Anéis/química , Humanos , Modelos Moleculares , Estrutura Molecular , Relação Estrutura-Atividade
10.
Future Med Chem ; 9(8): 731-748, 2017 05.
Artigo em Inglês | MEDLINE | ID: mdl-28485668

RESUMO

AIM: Since neuroinflammation is partially mediated by cAMP levels and PDE10A enzyme is able to regulate these levels being highly expressed in striatum, its inhibitors emerged as useful drugs to mitigate this inflammatory process and hence the neuronal death associated with Parkinson's disease (PD). Methodology & results: To study the utility of PDE10A as a pharmacological target for PD, in this work we propose the search and development of new PDE10A inhibitors that could be useful as pharmacological tools in models of the disease and presumably as potential drug candidates. By using different medicinal chemistry approaches we have discovered imidazole-like PDE10A inhibitors and showed their neuroprotective actions. CONCLUSION: Here, we demonstrate the neuroprotective effect of PDE10A inhibitors in cellular models of PD. [Formula: see text].


Assuntos
Imidazóis/farmacologia , Doença de Parkinson/tratamento farmacológico , Inibidores de Fosfodiesterase/farmacologia , Diester Fosfórico Hidrolases/metabolismo , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Humanos , Imidazóis/síntese química , Imidazóis/química , Modelos Moleculares , Estrutura Molecular , Doença de Parkinson/metabolismo , Inibidores de Fosfodiesterase/síntese química , Inibidores de Fosfodiesterase/química
11.
FEBS J ; 283(2): 305-22, 2016 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-26499089

RESUMO

UNLABELLED: A unique defense mechanisms by which Mycobacterium tuberculosis protects itself from nitrosative stress is based on the O2 -dependent NO-dioxygenase (NOD) activity of truncated hemoglobin 2/2HbN (Mt2/2HbN). The NOD activity largely depends on the efficiency of ligand migration to the heme cavity through a two-tunnel (long and short) system; recently, it was also correlated with the presence at the Mt2/2HbN N-terminus of a short pre-A region, not conserved in most 2/2HbNs, whose deletion results in a drastic reduction of NO scavenging. In the present study, we report the crystal structure of Mt2/2HbN-ΔpreA, lacking the pre-A region, at a resolution of 1.53 Å. We show that removal of the pre-A region results in long range effects on the protein C-terminus, promoting the assembly of a stable dimer, both in the crystals and in solution. In the Mt2/2HbN-ΔpreA dimer, access of heme ligands to the short tunnel is hindered. Molecular dynamics simulations show that the long tunnel branch is the only accessible pathway for O2 -ligand migration to/from the heme, and that the gating residue Phe(62)E15 partly restricts the diameter of the tunnel. Accordingly, kinetic measurements indicate that the kon value for peroxynitrite isomerization by Mt2/2HbN-ΔpreA-Fe(III) is four-fold lower relative to the full-length protein, and that NO scavenging by Mt2/2HbN-ΔpreA-Fe(II)-O2 is reduced by 35-fold. Therefore, we speculate that Mt2/2HbN evolved to host the pre-A region as a mechanism for preventing dimerization, thus reinforcing the survival of the microorganism against the reactive nitrosative stress in macrophages. DATABASE: Coordinates and structure factors have been deposited in the Protein Data Bank under accession number 5AB8.


Assuntos
Proteínas de Bactérias/metabolismo , Mycobacterium tuberculosis/metabolismo , Hemoglobinas Truncadas/metabolismo , Proteínas de Bactérias/genética , Cristalografia por Raios X , Dioxigenases/metabolismo , Heme/química , Heme/metabolismo , Cinética , Simulação de Dinâmica Molecular , Mutação , Óxido Nítrico/metabolismo , Ácido Peroxinitroso/química , Ácido Peroxinitroso/metabolismo , Conformação Proteica , Multimerização Proteica , Hemoglobinas Truncadas/genética
12.
Chemistry ; 21(40): 14036-46, 2015 Sep 28.
Artigo em Inglês | MEDLINE | ID: mdl-26376331

RESUMO

Two domino Diels-Alder adducts were obtained from 3,7-bis(cyclopenta-2,4-dien-1-ylidene)-cis-bicyclo[3.3.0]octane and dimethyl acetylenedicarboxylate or N-methylmaleimide under microwave irradiation. From the first adduct, a C20H24 diene with C2v symmetry was obtained by Zn/AcOH reduction, hydrolysis, oxidative decarboxylation, and selective hydrogenation. Photochemical [2+2] cycloaddition of this diene gave a thermally unstable cyclobutane derivative, which reverts to the diene. However, both the diene and the cyclobutane derivatives could be identified by X-ray diffraction analysis upon irradiation of the diene crystal. New six-membered rings are formed upon the transannular addition of bromine or iodine to the diene. The N-type selectivity of the addition was examined by theoretical calculations, which revealed the distinct susceptibility of the doubly bonded carbon atoms to the bromine attack.

13.
IUBMB Life ; 63(5): 355-62, 2011 May.
Artigo em Inglês | MEDLINE | ID: mdl-21618402

RESUMO

Nonsymbiotic hemoglobins AHb1 and AHb2 discovered in Arabidopsis thaliana are likely to carry out distinct physiological roles, in consideration of their differences in sequence, structure, expression pattern, and tissue localization. Despite a relatively fast autoxidation in the presence of O(2) , we were able to collect O(2) -binding curves for AHb2 in the presence of a reduction enzymatic system. AHb2 binds O(2) noncooperatively with a p50 of 0.021 ± 0.003 Torr, a value consistent with a recently proposed role in O(2) transport. The analysis of the internal cavities derived from the structures sampled in molecular dynamics simulations confirms strong differences with AHb1, proposed to work as a NO deoxygenase in vivo. Overall, our results are consistent with a role for AHb2 as an oxygen carrier, as recently proposed on the basis of experiments on AHb2-overexpressing mutants of A. thaliana.


Assuntos
Proteínas de Arabidopsis/metabolismo , Arabidopsis/fisiologia , Hemoglobinas/metabolismo , Oxigênio/metabolismo , Proteínas de Arabidopsis/química , Proteínas de Arabidopsis/genética , Transporte Biológico , Hemoglobinas/química , Hemoglobinas/genética , Modelos Moleculares , Simulação de Dinâmica Molecular , Oxirredução , Ligação Proteica , Conformação Proteica
14.
J Mol Model ; 13(2): 357-65, 2007 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-17024407

RESUMO

We investigate the changes in the solvation properties of the natural nucleic acid bases due to the formation of the canonical Watson-Crick hydrogen-bonded complexes. To this end, the changes in the free energy of solvation of the bases induced upon hydrogen-bonded dimerization are analyzed by means of the hydrophobic similarity index, which relies on the atomic contributions to the free energy of solvation determined by the partitioning method implemented in the framework of the MST continuum model. Such an index is also used to examine the hydrophobic similarity between the canonical nucleic acid bases and a series of highly apolar analogues, which have been designed as potential candidates to expand the genetic alphabet. The ability of these analogues to be incorporated into modified DNA duplexes can be related to the large reduction in the hydrophilicity of the natural bases upon formation of the canonical hydrogen-bonded dimers. The results illustrate the suitability of the hydrophobic similarity index to rationalize the role played by solvation in molecular recognition.


Assuntos
Interações Hidrofóbicas e Hidrofílicas , Modelos Moleculares , Ácidos Nucleicos/química , Purinas/química , Pirimidinas/química
15.
J Med Chem ; 49(23): 6833-40, 2006 Nov 16.
Artigo em Inglês | MEDLINE | ID: mdl-17154513

RESUMO

The acetylcholinesterase (AChE) inhibitory activity of a series of 13-amido derivatives of huprine Y, designed to enlarge the occupancy of the catalytic binding site by mimicking the piridone moiety present in (-)-huperzine A, has been assessed. Although both 13-formamido and 13-methanesulfonamido derivatives are more potent human AChE inhibitors than tacrine and (-)-huperzine A, none of them equals the potency of huprine Y. Molecular modeling studies show that the two derivatives effectively trigger the Gly117-Gly118 conformational flip induced upon binding of (-)-huperzine A, leading to a similar pattern of interactions as that formed by the pyridone amido group of (-)-huperzine A. The detrimental effect on the binding affinity relative to the 13-unsubstituted huprine could be ascribed to a sizable deformation cost associated with the ligand-induced peptide flip. This finding can be interpreted as a mechanism selected by evolution to ensure the preorganization of the functionally relevant oxyanion hole in the binding site of AChE, where residues Gly117 and Gly118 play a relevant role in mediating substrate recognition.


Assuntos
Acetilcolinesterase/química , Aminoquinolinas/química , Inibidores da Colinesterase/química , Glicina/química , Compostos Heterocíclicos de 4 ou mais Anéis/química , Alcaloides , Animais , Ânions , Domínio Catalítico , Bovinos , Eritrócitos/enzimologia , Formamidas/química , Humanos , Ligantes , Modelos Moleculares , Ligação Proteica , Conformação Proteica , Sesquiterpenos/química , Estereoisomerismo , Relação Estrutura-Atividade , Sulfonamidas/química , Tacrina/química
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