Inverse virtual screening studies of selected natural compounds from cerrado

Abstract

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 stepforming 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.

Virtual screening: An in silico tool for interlacing the chemical universe with the proteome

“…induced fit), (iv) to calculate binding free energies, (v) to provide an accurate ranking of the potential ligands, or (vi) during the docking process itself (to find the binding site and correctly dock the ligand) [127]. In the IVS examples discussed here, MD was used previously to docking for sampling the conformational space [128] or afterwards to discard false positives [129]. Particularly, docking followed by relaxation and minimization by MD can be performed [130] to provide a dynamic picture which helps to distinguish correctly docked conformations from the unstable ones.…”

“…IVS is also increasingly applied to target discovery of natural compounds [129,158,179,180]. For example, Carregal et al [129] have used Autodock Vina for IVS with the sc-PDB, followed by 1 ns implicit solvent MD to discard false positive targets of five natural products. Single-point QM/MM ONIOM (PM6:UFF) calculations [181] were then performed to successfully determine their binding energy within these targets.…”

Brazilian malaria molecular targets (BraMMT): selected receptors for virtual high-throughput screening experiments

“…Virtual screening (VS) became widely used in 1990 during the initial phases of research into the drug discovery process for the identification and selection of new bioactive molecules. 9 In this study, VS is denoted as virtual high-throughput screening (vHTS). Specifically, vHTS is a computational method of molecular docking to predict the molecular target of ligands by estimating their binding affinity.…”

NS2B-NS3pro como Alvo Molecular para o Desenvolvimento de Fármacos contra Dengue

“…Esta busca um determinado alvo molecular (não necessariamente a NS2B-NS3pro) por métodos de triagem experimental. Por outro lado, a triagem virtual aplica metodologias in silico bastante rápidas para encontrar novos compostos protótipos, porém esta também possui as limitações tais como falsos positivos e pouca diversidade estrutural (quando comparado aos produtos naturais) (CARREGAL et al, 2012;CARREGAL;COMAR JUNIOR;TARANTO, 2013). Esta busca de ligantes em banco de dados possibilita o rastreamento de milhares de compostos para um alvo molecular específico.…”