Computational Study of the interaction of acridine derivatives with DNA

• Autor(a) principal: Pedro, Maria Beatriz Pinto Lopes
• Data de Publicação: 2020
• Tipo de documento: Dissertação
• Idioma: eng
• Título da fonte: Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos)
• Texto Completo: http://hdl.handle.net/10773/29324
• topic: Cancer; DNA; Intercalation; Acridine derivatives; Molecular docking

DNA is a significant target for the treatment of many diseases, including cancer. DNA intercalation is the process by which small molecules containing planar aromatic or heteroaromatic systems, are inserted between the adjacent DNA base pairs. Intercalation leads to many conformational changes in DNA with concomitant interference with its biological functions. Experimental procedures to evaluate the binding mode between drug candidates and DNA involve risks and are time and money consuming. These drawbacks can be avoided with the use of computer-aided techniques. Acridines and its derivatives have been showing great potential in developing new antitumoral drugs mainly due to their DNA-intercalative properties, which are enhanced by their acceptor/donor nitrogen atoms and planar structure. The antiproliferative properties may be altered upon grafting different ligands into the acridine ring, making them useful moieties for the development of target-based drug discovery. Molecular docking techniques allows the prediction of the most probable orientation of drug candidates against their targets and the corresponding binding affinities. The studies can be complemented with results from molecular dynamics (MD) simulations for further validation under more realistic conditions. Therefore, molecular docking and MD simulations may be employed to better understand the relationship between different substituents and the affinities of the resulting compounds to DNA, hence, to anticipate their antitumoral potential. In this work, computational tools, docking and molecular dynamics, were used to study the interaction of three acridine derivatives (compounds 5a-c) with five different DNA models. Through the results it was possible to infer which modes of interaction with DNA were possible for each compound: threading intercalation for compound 5a, minor groove and threading intercalation for compound 5b, and minor groove or classic intercalation for compound 5c.