RESUMO
We report here two new small-size peptides acting as modulators of the ß-site APP cleaving enzyme 1 (BACE1) exosite. Ac-YPYFDPL-NH2 and Ac-YPYDIPL-NH2 displayed a moderate but significant inhibitory effect on BACE1. These peptides were obtained from a molecular modeling study. By combining MD simulations with ab initio and DFT calculations, a simple and generally applicable procedure to evaluate the binding energies of small-size peptides interacting with the exosite of the BACE1 is reported here. The structural aspects obtained for the different complexes were analyzed providing a clear picture about the binding interactions of these peptides. These interactions have been investigated within the framework of the density functional theory and the quantum theory of atoms in molecules using a reduced model. Although the approach used here was traditionally applied to the study of noncovalent interactions in small molecules complexes in gas phase, we show, through in this work, that this methodology is also a very powerful tool for the study of biomolecular complexes, providing a very detailed description of the binding event of peptides modulators at the exosite of BACE1.
Assuntos
Secretases da Proteína Precursora do Amiloide/química , Ácido Aspártico Endopeptidases/química , Sítios de Ligação , Desenho de Fármacos , Modelos Moleculares , Peptídeos/química , Humanos , Conformação Molecular , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Domínios e Motivos de Interação entre Proteínas , Relação Quantitativa Estrutura-AtividadeRESUMO
The synthesis, in vitro evaluation and conformational study of penetratin and structurally related derivatives acting as antibacterial agents are reported. Among the compounds evaluated here, two methionine sulphoxide derivatives (RQIKIWFQNRRM[O]KWKK-NH2 and RQIKIFFQNRRM[O]KFKK-NH2 ) exhibited the strongest antibacterial effect in this series. In order to better understand the antimicrobial activity obtained for these peptides, we performed an exhaustive conformational analysis using different approaches. Molecular dynamics simulations were performed using two different media (water and trifluoroethanol/water). The results of these theoretical calculations were corroborated using experimental CD measurements. The electronic study for these peptides was carried out using molecular electrostatic potentials obtained from RHF/6-31G(d) calculations. In addition, the non-apeptide RQIRRWWQR-NH2 showed strong inhibitory action against the Gram-negative and Gram-positive bacteria tested in this study.
Assuntos
Antibacterianos/química , Antibacterianos/farmacologia , Proteínas de Transporte/química , Proteínas de Transporte/farmacologia , Sequência de Aminoácidos , Infecções Bacterianas/tratamento farmacológico , Peptídeos Penetradores de Células , Humanos , Modelos Moleculares , Dados de Sequência Molecular , Conformação ProteicaRESUMO
The synthesis, in vitro evaluation, and conformational study of penetratin analogues acting as antifungal agents are reported. Different peptides structurally related with penetratin were evaluated. Analogues of penetratin rich in Arg, Lys and Trp amino acids were tested. In addition, HFRWRQIKIWFQNRRM[O]KWKK-NH(2), a synthetic 20 amino acid peptide was also evaluated. These penetratin analogues displayed antifungal activity against human pathogenic strains including Candida albicans and Cryptococcus neoformans. In contrast, Tat peptide, a well-known cell penetrating peptide, did not show a significant antifungal activity against fungus tested here. We also performed a conformational study by means experimental and theoretical approaches (CD spectroscopic measurements and MD simulations). The electronic structure analysis was carried out from Molecular Electrostatic Potentials (MEP) obtained by using RHF/6-31G ab initio calculations. Our experimental and theoretical results permitted us to identify a topographical template which may provide a guide for the design of new peptides with antifungal effects.
Assuntos
Antifúngicos/química , Antifúngicos/farmacologia , Proteínas de Transporte/química , Proteínas de Transporte/farmacologia , Fungos/efeitos dos fármacos , Sequência de Aminoácidos , Peptídeos Penetradores de Células , Dicroísmo Circular , Simulação de Dinâmica Molecular , Dados de Sequência Molecular , Método de Monte Carlo , Conformação Proteica , Eletricidade EstáticaRESUMO
The synthesis, in vitro evaluation and conformational study of KKWKMRRNQFWIKIQR-NH(2), HFRWRQIKIWFQNRRMKWKK-NH(2) and RQPKIWFPNRRKPWKK-NH(2) acting as antifungal agents are reported. These peptides displayed a moderate but significant antifungal effect against both pathogenic fungi Candida albicans and Cryptococcus neoformans. The conformational analysis of these peptides was carried out using both theoretical and experimental methods.
Assuntos
Antifúngicos/síntese química , Peptídeos/síntese química , Sequência de Aminoácidos , Antifúngicos/química , Antifúngicos/farmacologia , Candida albicans/efeitos dos fármacos , Dicroísmo Circular , Cryptococcus neoformans/efeitos dos fármacos , Testes de Sensibilidade Microbiana , Dados de Sequência Molecular , Peptídeos/química , Peptídeos/farmacologia , Estrutura Secundária de ProteínaRESUMO
The synthesis, in vitro evaluation, and conformational study of a new series of small-size peptides acting as antifungal agents are reported. In a first step of our study we performed a conformational analysis using Molecular Mechanics calculations. The electronic study was carried out using Molecular electrostatic potentials (MEPs) obtained from RHF/6-31G calculations. On the basis of the theoretical predictions three small-size peptides, RQWKKWWQWRR-NH(2), RQIRRWWQWRR-NH(2), and RQIRRWWQW-NH(2) were synthesized and tested. These peptides displayed a significant antifungal activity against human pathogenic strains including Candida albicans and Cryptococcus neoformans. Our experimental and theoretical results allow the identification of a topographical template which can serve as a guide for the design of new compounds with antifungal properties for potential therapeutic applications against these pathogenic fungi.
Assuntos
Antifúngicos/química , Antifúngicos/farmacologia , Candida albicans/efeitos dos fármacos , Cryptococcus neoformans/efeitos dos fármacos , Micoses/tratamento farmacológico , Peptídeos/química , Peptídeos/farmacologia , Sequência de Aminoácidos , Animais , Antifúngicos/toxicidade , Candidíase/tratamento farmacológico , Criptococose/tratamento farmacológico , Modelos Moleculares , Peptídeos/toxicidade , Poecilia , Testes de Toxicidade AgudaRESUMO
The synthesis, in vitro evaluation, and conformational study of RQIKIWFQNRRMKWKK-NH(2) (penetratin) and related derivatives acting as antifungal agents are reported. Penetratin and some of its derivatives displayed antifungal activity against the human opportunistic pathogenic standardized ATCC strains Candida albicans and Cryptococcus neoformans as well as clinical isolates of C. neoformans. Among the compounds tested, penetratin along with the nonapeptide RKWRRKWKK-NH(2) and the tetrapeptide RQKK-NH(2) exhibited significant antifungal activities against the Cryptococcus species. A comprehensive conformational analysis on the peptides reported here using three different approaches, molecular mechanics, simulated annealing and molecular dynamics simulations, was carried out. The experimental and theoretical results allow us to identify a topographical template which may provide a guide for the design of new compounds with antifungal characteristics against C. neoformans.
Assuntos
Antifúngicos/síntese química , Proteínas de Transporte/síntese química , Oligopeptídeos/síntese química , Sequência de Aminoácidos , Antifúngicos/farmacologia , Candida albicans/efeitos dos fármacos , Proteínas de Transporte/farmacologia , Peptídeos Penetradores de Células , Cryptococcus neoformans/efeitos dos fármacos , Humanos , Conformação Molecular , Oligopeptídeos/farmacologia , Relação Estrutura-AtividadeRESUMO
The synthesis, in vitro evaluation and conformational study of His-Phe-Arg-Trp-Gly-Lys-Pro-Val-NH(2) and analogues acting as antifungal agents are reported. Among them, His-Phe-Lys-Trp-Gly-Arg-Phe-Val-NH(2) exhibited a moderate but significant antifungal activity against Cryptococcus neoformans, Candida albicans and Candida tropicalis. A theoretical study allows us to propose a biologically relevant conformation for these octapeptides acting as antifungal agents. In addition, these theoretical calculations allow us to determine the minimal structural requirements to produce the antifungal response and can provide a guide for the design of compounds with this biological activity.
Assuntos
Antifúngicos/síntese química , Antifúngicos/farmacologia , Peptídeos/síntese química , Peptídeos/farmacologia , Sequência de Aminoácidos , Antifúngicos/química , Candida albicans/efeitos dos fármacos , Candida tropicalis/efeitos dos fármacos , Cryptococcus neoformans/efeitos dos fármacos , Modelos Moleculares , Conformação Molecular , Peptídeos/química , Eletricidade Estática , Relação Estrutura-AtividadeRESUMO
The synthesis, in vitro evaluation, and conformational study of His-Phe-Arg-Trp-NH2 and related derivatives acting as antifungal agents are reported. Among them, His-Phe-Arg-Trp-NH2 and His-Tyr-Arg-Trp-NH2 exhibited antifungal activity against Cryptococcus neoformans. Antifungal activity of these compounds appears to be closely related to the alpha-MSH effect. A conformational and electronic study allows us to propose a biologically relevant conformation for these tetrapeptides acting as antifungal agents. In addition, these theoretical calculations permit us to determine the minimal structural requirements to produce the antifungal response and may provide a guide for the design of compounds with this biological activity.