Avaliação in silico do potencial de intercalação de DNA para aplicação em biossensores por meio de docking molecular

Abstract

The DNA structure has an intrinsic conformational flexibility that is fundamental to understanding its organization and biological functions. Among the interactions highlighting this characteristic, intercalation stands out as a non-covalent mechanism where generally planar and aromatic molecules insert themselves between adjacent base pairs of the double helix. This process induces significant structural modifications, such as unwinding and elongation of the strand, which may interfere with vital cellular processes like replication and transcription. Given the biological and toxicological relevance of these interactions, evaluating the intercalating potential is crucial for understanding mechanisms of action, ensuring pharmaceutical safety, and developing biosensors. In this scenario, the use of in silico methods, such as molecular docking, allows for the three-dimensional modeling and quantification of the stability of these interactions, aiding in the prediction of the efficacy and genotoxicity of new compounds of biotechnological interest. The selection of molecules with intercalation capacity was performed through a screening of the NuBBE and PubChem databases, using a structure similar to the ethidium bromide biosensor as a research model. The study employed the Autodock Vina software for directed docking and blind docking against the DNA receptor (PDB 2ROU), validating the energetic preference for the identified binding sites. Furthermore, toxicity analyses for Ames mutagenicity and skin sensitization were conducted via the pkCSM platform, in addition to the visualization of 2D intermolecular interactions. The results allowed for the ranking of 17 compounds with affinities superior to the ethidium bromide control, with molecule 14771754 being a highlight. This compound exhibited favorable binding energy, a consistent binding mode, and an absence of mutagenicity, distinguishing itself from other candidates that, despite higher affinity, showed mutagenic potential.