RESUMO
A docking protocol aimed at obtaining a consistent qualitative and quantitative picture of binding for a series of hERG channel blockers is presented. To overcome the limitations experienced by standard procedures when docking blockers at hERG binding site, we designed a strategy that explicitly takes into account the conformations of the channel, their possible intrinsic symmetry, and the role played by the configurational entropy of ligands. The protocol was developed on a series of congeneric sertindole derivatives, allowing us to satisfactorily explain the structure-activity relationships for this set of blockers. In addition, we show that the performance of structure-based models relying on multiple-receptor conformations statistically increases when the protein conformations are chosen in such a way as to capture relevant structural features at the binding site. The protocol was then successfully applied to a series of structurally unrelated blockers.
Assuntos
Canais de Potássio Éter-A-Go-Go/antagonistas & inibidores , Canais de Potássio Éter-A-Go-Go/metabolismo , Simulação de Acoplamento Molecular/métodos , Bloqueadores dos Canais de Potássio/metabolismo , Bloqueadores dos Canais de Potássio/farmacologia , Automação , Canal de Potássio ERG1 , Canais de Potássio Éter-A-Go-Go/química , Humanos , Bloqueadores dos Canais de Potássio/química , Conformação Proteica , Solventes/química , Relação Estrutura-Atividade , TermodinâmicaRESUMO
The inward rectifier voltage-gated potassium channel hERG is of primary importance for the regulation of the membrane potential of cardiomyocytes. Unlike most voltage-gated K(+)-channels, hERG shows a low elementary conductance at physiological voltage and potassium concentration. To investigate the molecular features underlying this unusual behavior, we simulated the ion conduction through the selectivity filter at a fully atomistic level by means of molecular dynamics-based methods, using a homology-derived model. According to our calculations, permeation of potassium ions can occur along two pathways, one involving site vacancies inside the filter (showing an energy barrier of about 6 kcal mol(-1)), and the other characterized by the presence of a knock-on intermediate (about 8 kcal mol(-1)). These barriers are indeed in accordance with a low conductance behavior, and can be explained in terms of a series of distinctive structural features displayed by the hERG ion permeation pathway.
Assuntos
Canais de Potássio Éter-A-Go-Go/metabolismo , Íons , Simulação por Computador , Cristalografia por Raios X/métodos , Canal de Potássio ERG1 , Condutividade Elétrica , Eletrofisiologia , Humanos , Ativação do Canal Iônico/fisiologia , Bicamadas Lipídicas/química , Potenciais da Membrana , Modelos Biológicos , Modelos Moleculares , Conformação Molecular , Movimento (Física) , Potássio/químicaRESUMO
Molecular knowledge of hERG blocking liability can offer the possibility of optimizing lead compounds in a way that eliminates potentially lethal side effects. In this study, we computationally designed, synthesized, and tested a small series of "minimally structured" molecules. Some of these compounds were remarkably potent against hERG (6, IC(50) = 2.4 nM), allowing us to identify the minimal structural requirements for hERG blocking liability.
Assuntos
Canais de Potássio Éter-A-Go-Go/efeitos dos fármacos , Bloqueadores dos Canais de Potássio/síntese química , Desenho de Fármacos , Humanos , Síndrome do QT Longo/induzido quimicamente , Bloqueadores dos Canais de Potássio/efeitos adversos , Relação Quantitativa Estrutura-AtividadeAssuntos
Acetilcolinesterase/química , Amiloide/química , Inibidores da Colinesterase/química , Tacrina/análogos & derivados , Acetilcolinesterase/metabolismo , Amiloide/metabolismo , Secretases da Proteína Precursora do Amiloide/antagonistas & inibidores , Secretases da Proteína Precursora do Amiloide/metabolismo , Ácido Aspártico Endopeptidases/antagonistas & inibidores , Ácido Aspártico Endopeptidases/metabolismo , Sítios de Ligação , Inibidores da Colinesterase/síntese química , Inibidores da Colinesterase/farmacologia , Simulação por Computador , Desenho de Fármacos , Humanos , Ligantes , Tacrina/síntese química , Tacrina/química , Tacrina/farmacologiaRESUMO
We report on a series of hybrid compounds structurally derived from donepezil and AP2238. This study was aimed at improving the activities of the reference compounds, donepezil and AP2238, and at broadening the range of activities of new derivatives as, due to the multifactorial nature of AD, molecules that modulate the activity of a single protein target are unable to significantly modify the progression of the disease. In particular, the indanone core from donepezil was linked to the phenyl-N-methylbenzylamino moiety from AP2238, through a double bond that was kept to evaluate the role of a lower flexibility in the biological activities. Moreover, SAR studies were performed to evaluate the role of different substituents in position 5 or 6 of the indanone ring in the interaction with the PAS, introducing also alkyl chains of different lengths carrying different amines at one end. Derivatives 21 and 22 proved to be the most active within the series and their potencies against AChE were in the same order of magnitude of the reference compounds. Compounds 15, 21-22, with a 5-carbon alkyl chain bearing an amino moiety at one end, better contacting the PAS, remarkably improved the inhibition of AChE-induced Abeta aggregation with respect to the reference compounds. They also showed activity against self-aggregation of Abeta(42) peptide, the most amyloidogenic form of amyloid produced in AD brains, while the reference compounds resulted completely ineffective.
Assuntos
Doença de Alzheimer/tratamento farmacológico , Benzilaminas/química , Cumarínicos/química , Indanos/química , Tetra-Hidronaftalenos/química , Acetilcolinesterase/química , Acetilcolinesterase/genética , Acetilcolinesterase/metabolismo , Peptídeos beta-Amiloides/metabolismo , Protocolos de Quimioterapia Combinada Antineoplásica , Benzilaminas/síntese química , Benzilaminas/uso terapêutico , Sítios de Ligação , Bleomicina , Inibidores da Colinesterase/síntese química , Inibidores da Colinesterase/química , Inibidores da Colinesterase/uso terapêutico , Simulação por Computador , Cumarínicos/uso terapêutico , Donepezila , Humanos , Indanos/uso terapêutico , Lomustina , Metotrexato , Fragmentos de Peptídeos/metabolismo , Piperidinas/química , Piperidinas/uso terapêutico , Proteínas Recombinantes/química , Proteínas Recombinantes/genética , Proteínas Recombinantes/metabolismo , Estilbenos , Relação Estrutura-Atividade , Tetra-Hidronaftalenos/síntese química , Tetra-Hidronaftalenos/uso terapêuticoRESUMO
BACKGROUND: hERG K(+) channels have been recognized as a primary antitarget in safety pharmacology. Their blockade, caused by several drugs with different therapeutic indications, may lead to QT prolongation and, eventually, to potentially fatal arrhythmia, namely torsade de pointes. Therefore, a number of preclinical models have been developed to predict hERG liability early in the drug development process. OBJECTIVE: The aim of this review is to outline the present state of the art on drug-induced hERG blockade, providing insights on the predictive value of in vitro and in silico models for hERG liability. METHODS: On the basis of latest reports, high-throughput preclinical models have been discussed outlining advantages and limitations. CONCLUSION: Although no single model has an absolute value, an integrated risk assessment is recommended to predict the pro-arrhythmic risk of a given drug. This prediction requires expertise from different areas and should encompass emerging issues such as interference with hERG trafficking and QT shortening.
Assuntos
Avaliação Pré-Clínica de Medicamentos/métodos , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos , Canais de Potássio Éter-A-Go-Go/efeitos dos fármacos , Torsades de Pointes/induzido quimicamente , Animais , Canal de Potássio ERG1 , Humanos , Medição de Risco/métodosRESUMO
Structure-activity relationship studies on acetylcholinesterase (AChE) inhibitors were extended to newly synthesized compounds derived from the lead compound xantostigmine (1). The xanthone ring of compound 1 was replaced with several different scaffolds based on the benzopyran skeleton, linked to the tertiary amino nitrogen through an heptyloxy chain. These modifications resulted in 19 new compounds, most of them showing activity in the nanomolar-subnanomolar range. Docking and molecular dynamics simulations were carried out to both define a new computational protocol for the simulation of pseudo-irreversibile AChE covalent inhibitors, and to acquire a better understanding of the structure-activity relationships of the present series of compounds. The results of this computational work prompted us to to evaluate the ability of compounds 5 and 13 to inhibit acetylcholinesterase-induced Abeta aggregation.
Assuntos
Acetilcolinesterase/metabolismo , Inibidores da Colinesterase/síntese química , Inibidores da Colinesterase/farmacologia , Xantonas/síntese química , Xantonas/farmacologia , Domínio Catalítico , Inibidores da Colinesterase/química , Simulação por Computador , Humanos , Modelos Moleculares , Estrutura Molecular , Ligação Proteica , Relação Estrutura-Atividade , Xantonas/químicaRESUMO
Alzheimer's disease (AD) is a multifactorial syndrome with several target proteins contributing to its etiology. To confront AD, an innovative strategy is to design single chemical entities able to simultaneously modulate more than one target. Here, we present compounds that inhibit acetylcholinesterase and NMDA receptor activity. Furthermore, these compounds inhibit AChE-induced Abeta aggregation and display antioxidant properties, emerging as lead candidates for treating AD.