Avaliação in silico do potencial farmacológico e toxicológico de friedelanos, lupanos e derivados

Abstract

Potential targets and biological effects and some physicochemical properties related to ADMET were studied in relation to 28 pentacyclic triterpenes, being 14 of the friedelane series and 14 of the lupane series, using in silico computational tools. In the virtual screening used for identification of potential targets and biological effects were used the tools PASS online and ChemMapper based on structure of active compounds, molecular docking (Surflex software) and on the structures of biological targets identified by means of previously reported data. For molecular dockin of pentacyclic triterpenes were constructed two databases, being one related to biological targets and other containing active and inactive ligands targets. The targets were selected in accordance to those related to biological activities attributed to pentacyclic triterpenes of different series. To validate the data of target base was used the RMSD calculus, by means of which was found significant correlation between the most probable conformations, indicated by molecular docking, with those available in crystallographic files. A comparison was also made between the results of affinity index calculated using the software Surflex, with the results of in vitro and/or in vivo assays available in cientific literature. An analysis of the difference between the probability of the pentacyclic triterpene be active (compared with active ligands) and the probability of be inactive (compared to inactive binders) also was done. Through the obtained data was attributed for some pentacyclic triterpenes high chance of being active against enzyme adenosine deaminase, cytochrome P450 19a1, DNA topoisomerase II, glutamate dehydrogenase, glutathione S-transferase, HIV-1 integrase and HIV-1 protease. These targets are associated to antitumor effects via apoptosis induction or cell division inhibition, and anti-parasite and antiviral activities. The analysis of the listed targets and biological effects obtained through ChemMapper, PASSonline tools and also by molecular docking were correspondent to those available in literature. The indications of potential antiprotozoal effect focused to Leishmania were compared with the results of in vitro assays related to inhibition of extracellular forms of Leishmania amazonensis. A marked degree of correlation in the results obtained in vitro assays with in silico tests using molecular docking and PASSonline tool was found. Through the in silico analysis, to 4-O-methylepigalocatequin, tingenone and pro-antocianidin A, constituents isolated from Maytenus gonoclada Mart were attributed potential effects such as antiviral and apoptosis induction. As a result, poliovirus infected VERO cells were treated with these compounds to check its possible antiviral effect. Also were subjected to antiviral assays crude ethanolic extracts from leaves, stems and roots of M. gonoclada, from which the constituents were isolated. High cytotoxicity for VERO cells was observed for tingenone associated to induction of apoptosis. For the other two constituents was detected low induction of apoptosis. None of the extracts or pure compounds tested showed anti-Poliovirus activity. These results were in accordance with those found through PASS online and ChemMapper which indicated mainly induction of cellular apoptosis effect. Through the results obtained in present work for friedelanes and lupanes was demonstrated an adequate applicability degree of the in silico tools PASS online and ChemMapper for studies involving news series of pentacyclic triterpenes such as ursanes, oleananes, taraxanes and others.