Inclusão da flexibilidade do receptor no programa DockThor através da abordagem de Soft Docking

• Autor(a) principal: Karl, Ana Luiza Martins
• Data de Publicação: 2019
• Tipo de documento: Dissertação
• Idioma: por
• Título da fonte: Biblioteca Digital de Teses e Dissertações do LNCC
• Texto Completo: https://tede.lncc.br/handle/tede/310
• topic: Farmacologia; Simulação de acoplamento molecular; DockThor (Programa de computador); CNPQ::CIENCIAS BIOLOGICAS::FARMACOLOGIA

With the improvement of computational power, computational techniques have been gaining increasing importance in pharmaceutical research, since they contribute to the reduction of time and cost in the planning of new drugs. The computational methodology known as molecular docking aims to predict binding modes and binding affinity of a small molecule (ligand) at the binding site of the biological target of interest (receptor). One of the great challenges of the area is the treatment of receptor flexibility, which – because it has many degrees of freedom – is difficult to be represented computationally. Thus, the receptor is usually treated as a rigid structure, as is currently done in the DockThor docking program, used in the present work. One of the simplest ways to handle receptor flexibility in docking methodology is through the soft-docking technique, which consists in softening the van der Waals potential, a common part of the evaluation function of docking programs. The DockThor program uses a function based on the MMFF94S force field as an evaluation function for the prediction of binding modes. Therefore, the present work consists in the development of a new version of the DockThor program that considers the flexibility of receptors through the soft docking technique. Experiments of redocking and crossdocking were performed in test sets with different characteristics to validate the strategy and to explore different degrees of softening. In general, the inclusion of the smoothed potential maintained or slightly improved results for the investigated sets. In crossdocking assays, the inclusion of the soft docking strategy demonstrated great potential for improvement in pose prediction, using single or multiple structures of the receptor in docking studies. Improvements in pose prediction due to the insertion of the soft docking approach were also able to yield slight improvements in binding affinity prediction. The inclusion of this new methodology makes the DockThor program even more robust for receptor-ligand interactions studies, contributing to the academic community and research groups in the field of drug design.