MIA-QSAR MODELING biological activity of inhibitors of phosphodiesterase type-5. / Modelagem Mia-Qsar das atividades biolÃgicas de inibidores de fosfodiesterase tipo-5.

AUTOR(ES)
DATA DE PUBLICAÇÃO

2009

RESUMO

The use of theoretical models to represent and manipulate molecular structures, study chemical reactions and establish relationships between structure and matter properties constitutes the field of application of molecular modeling. In this context, several molecular modeling methods have been developed and should be tested and validated in regard to its applicability. In the first part of this work, a molecular modeling method, which correlates quantitatively a chemical structure with its biological activity through multivariate image analysis (MIA-QSAR), was evaluated. A model was built from a series of phosphodiesterase type-5 (PDE-5) inhibitors, useful compounds for the treatment of erectile dysfunction, and then compared with other methods of literature. Model calibration and validation was achieved through partial least squares (PLS) regression, demonstrating a high correlation between experimental and calculated data. Therefore, the model built was proved to be as efficient as the most sophisticated methods available today, such as CoMFA and CoMSIA, showing to be an advantageous alternative in many aspects in QSAR. In the second part, the MIA-QSAR method was evaluated in practice, to predict the inhibitory potency of novel phosphodiesterase type-5 inhibitors. A set of compounds derived from the structures of Sildenafil (ViagraÂ), Vardenafil (LevitraÂ) and Tadalafil (CialisÂ) was used in the building of the MIA-QSAR model. After model calibration and validation, new compounds were proposed and their activities estimated. From this pool, six new chemical structures showed to be promising drug-like compounds, because they exhibited high calculated inhibition toward PDE-5, such as the reference compounds (Sildenafil, Vardenafil and Tadalafil). A docking study was carried out to evaluate the affinity of the proposed compounds with the PDE-5 enzyme, and two additional compounds were submitted to the docking process. The interaction energies of the proposed and reference compounds were similar, showing good affinity toward the enzyme. The eight proposed compounds, plus the reference ones, were submitted to pharmacokinetic ADME-Tox studies (Absorption, Distribution, Metabolism, Excretion and Toxicity) by using the ADME and Tox boxes of the PharmaAlgorithms program. The results showed that the predicted compounds, especially two of them, presented satisfactory absorption and toxicity parameters, comparable or even better than the reference drugs. The MIA-QSAR method was shown to be as efficient as other ligand-based QSAR methods, demonstrating a great ability to estimate the biological activities of new PDE-5 inhibitors. By using different computational resources, this study was capable to propose new drugs, exemplifying the efficiency of computational chemistry as a tool to reduce time and cost during in the development of new drugs.

ASSUNTO(S)

quimica 1. disfunÃÃo erÃtil. 2. mia-qsar. 3. pls. 4. docking 5. inibidores da fosfodiesterase tipo-5 1. erectile dysfunction. 2. mia-qsar. 3. pls. 4. docking 5. inhibitors of phosphodiesterase type-5

ACESSO AO ARTIGO

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