Inverse virtual screening studies of selected natural compounds from cerrado

• Published in: International journal of quantum chemistry Vol. 112; no. 20; pp. 3333 - 3340
• Main Authors: Carregal, Ana Paula, Comar Jr, Moacyr, Alves, Stênio Nunes, Siqueira, João Máximo de, Lima, Luciana A., Taranto, Alex Gutterres
• Format: Journal Article
• Language: English
• Published: Hoboken Wiley Subscription Services, Inc., A Wiley Company 15.10.2012
• Subjects: inverse docking; IVS; natural products; ONIOM; QM/MM; sc-PDB
• ISSN: 0020-7608; 1097-461X
• DOI: 10.1002/qua.24205

Several medicinal plants have been studied in recent years in Brazil. However, despite many efforts, the pharmacological mechanisms of many natural products are still unknown. Several biological assays in vivo and in vitro are needed to further address this issue, which increases the cost of these studies. The main goal of this study was to apply the methodology of inverse virtual screening (IVS), followed by docking studies, and refinement by molecular dynamics (MD) simulation and quantum mechanical/molecular mechanical to determine the pharmacological receptors for five selected natural products with the exception of the benzoxazinone isolated from the exudate of the radicle of the crop species which were mainly isolated from the Cerrado species, obtained from Cerrado, a typical Brazilian biome. Initially, the structures of the natural compounds were generated using the online software program sc‐PDB, which searches for molecular targets deposited in the protein data bank. The ligands were docked against target proteins found in IVS step‐forming complexes, which were refined again using MD simulations by ff03 force field for 1 ns. Finally, the binding energy for each complex was obtained by the ONIOM (PM6:UFF) method. As a result, these calculations suggested possible molecular targets for these natural compounds. Among the targets found were 1EH4, 2A4Z, 1H49, 1JT2, 2BNJ, and 3FW9, which are involved in cancer and rheumatoid arthritis pathologies, indicating that they are promising molecular targets. In this study, we proposed a biological assay for these natural compounds. The results indicate that structural changes may be proposed to generate compounds that are able to bind more strongly to the receptor and become new drug candidates, thus optimizing the search for lead natural compounds. © 2012 Wiley Periodicals, Inc. Several medicinal plants have been studied in recent years in Brazil. However, the pharmacological mechanisms of many natural products are still unknown. In this study, inverse virtual screening (IVS), molecular dynamics simulation, and quantum mechanical/molecular mechanical, suggested pharmacological receptors for selected natural products. The identification and evaluation of these targets can be useful for predication the activity and toxicity of compounds. Thus, IVS can be considered as a new tool for structure‐based drug design.