Novel chalcones derivatives with potential antineoplastic activity investigated by docking and molecular dynamics simulations.

Glioblastoma is an aggressive primary tumor of the central nervous system (CNS). Is the most aggressive among infiltrative gliomas arising from the CNS. This tumor has low patient survival rate and several studies aiming at developing new drugs have increased. Patients with this cancer type face significant morbidity and mortality. This study evaluated the antineoplastic activity of synthetic chalcones (3a-3f) using in vitro glioblastoma models and molecular modeling. Cytotoxicity assay showed that Astrocitoma Hospital Ofir Loyola No 1 (AHOL1) and Uppsala 87 neoplastic glioblastoma lines (U87) cellular viability were significantly reduced compared to Healthy human fibroblasts cell lines (AN27) when exposed to chalcones. Interaction with the serine amino acid was present in the most promising and the reference binder docking, suggesting its importance inhibiting cell growth. Comparative analysis between the reference ligands and the molecules showed that the amino acid LYS352 present in all fittings, suggesting that this is the main amino acid for interaction with tubulin and are consistent with those in cytotoxicity assay, suggesting antineoplastic potential in glioblastoma. Long trajectory molecular dynamics studies were also carried out in order to investigate stability and conformations amongst the chalcones bound tubulin as well, in comparison to doxorubicin (here used as control), however future studies are needed to further assess the mechanism of inhibition of chalcones used in this investigation.Communicated by Ramaswamy H. Sarma.

Potential inhibitors of the enzyme acetylcholinesterase and juvenile hormone with insecticidal activity: study of the binding mode via docking and molecular dynamics simulations.

Models validation in QSAR, pharmacophore, docking and others can ensure the accuracy and reliability of future predictions in design and selection of molecules with biological activity. In this study, pyriproxyfen was used as a pivot/template to search the database of the Maybridge Database for potential inhibitors of the enzymes acetylcholinesterase and juvenile hormone as well. The initial virtual screening based on the 3D shape resulted in 2000 molecules with Tanimoto index ranging from 0.58 to 0.88. A new reclassification was performed on the overlapping of positive and negative charges, which resulted in 100 molecules with Tanimoto's electrostatic score ranging from 0.627 to 0.87. Using parameters related to absorption, distribution, metabolism and excretion and the pivot molecule, the molecules selected in the previous stage were evaluated regarding these criteria, and 21 were then selected. The pharmacokinetic and toxicological properties were considered and for 12 molecules, the DEREK software not fired any alert of toxicity, which were thus considered satisfactory for prediction of biological activity using the Web server PASS. In the molecular docking with insect acetylcholinesterase, the Maybridge3_002654 molecule had binding affinity of -11.1 kcal/mol, whereas in human acetylcholinesterase, the Maybridge4_001571molecule show in silico affinity of -10.2 kcal/mol, and in the juvenile hormone, the molecule MCULE-8839595892 show in silico affinity value of -11.6 kcal/mol. Subsequent long-trajectory molecular dynamics studies indicated considerable stability of the novel molecules compared to the controls.AbbreviationsQSARquantitative structure-activity relationshipsPASSprediction of activity spectra for substancesCommunicated by Ramaswamy H. Sarma.