8-O-4'-connected neolignans as antileishmanial agents: an exploration by molecular docking

• Published in: Planta Medica
• Main Authors: Ordúz-Díaz, LL, Barrera-Adame, DA, Coy-Barrera, ED
• Format: Conference Proceeding
• Language: English
• Published: 21.08.2013
• ISSN: 0032-0943; 1439-0221
• DOI: 10.1055/s-0033-1351914

A tropical infectious disease that still remains as a major cause of morbidity and mortality is Leishmaniasis produced by parasites of the genus Leishmania. Discovery of new drugs to control and treat that disease is practically incomplete. Thus, as part of our studies related to the search for therapeutic alternatives against Leishmania parasites, a molecular docking study was performed on a set of 8- O -4'-neolignan-like molecules in order to analyze the binding of this kind of neolignans on active sites of three main enzyme drug targets: farnesyl pyrophosphate synthase, trypanothione synthetase and N -myristoyltransferase. In order to observe the mode of binding, Autodock Vina was used to dock the most stable conformers of fifteen 8-O-4'-neolignans within the active site of Leishmania enzyme-based drug targets. Test structures were optimized at DFT level using B3LYP functional and 6 – 31G basis set. Stability of enzyme complexes between enzymes and neolignans were investigated through Vina scores and selected active site residues interactions. Good Vina scores were obtained for enzyme-ligand complexes interactions at different levels. Most stable conformer of neolignan 1 was found to exhibit the best Vina-score. In addition, the results indicated that the best poses were found to be different for each test compound as well as the active site residues involved into the ligand-enzyme binding. Residue-ligand interaction profile was correlated with Vina scores, exhibiting important structure-interaction relationships useful in further studies. Binding modes of 8-O-4'-neolignans into enzymes using ligand-protein docking were found to be different. This is the first study to provide an explanation at atomic level of the binding of this kind of neolignans into the above-mentioned enzymes. Further structural optimization of 8-O-4'-neolignans moieties should be considered in order to design antileishmanial agents.