Planejamento in silico e síntese de derivados do lupeol com atividade anti-inflamatória

Abstract

Inflammation is an immune system response against injury and pathogens and can lead to chronic disease when dysregulated. Historical studies, from Aulus Cornelius Celsus's cardinal signs to Rudolf Virchow's discovery of chemical mediators, have identified therapeutic targets in inflammation. Current research seeks innovation, including virtual drug screening to discover anti-inflammatory molecules. In turn, molecular modification can pharmacologically optimize substances, for example, triterpenes, present in several medicinal plants and which are capable of modulating inflammatory responses. The triterpene lupeol has antioxidant and anti-inflammatory activities, which can be exploited through semisynthesis. This study aimed to obtain lupeol derivatives capable of modulating the inflammatory response. To this end, rational planning was carried out to improve its original structure through molecular docking, the most promising molecules were synthesized and NMR was used for structural elucidation, and finally the pharmacokinetic, toxicity and molecular parameters of these compounds were investigated. In silico analyzes of binding affinity and cell permeability revealed promising features. Functional groups suggest covalent interactions, although they do not meet all the criteria of Lipinski's rule. Assessment of binding affinities highlights similarities with the reference ligand hydrocortisone cocrystallized with the enzyme code “2V95”, and compound 56 showed superior affinity. Despite the lower affinity of derivative 77 with the binding site, its classification as a substance that moderately crosses the blood-brain barrier opens doors for future analyses. The cellular permeability of lupeol derivatives indicates the potential to cross membranes, while the selective inhibition of CYP enzymes (56 and 73) influence the potential metabolism of other substances in the body. The inhibition of P-glycoprotein suggests that these molecules influence the prevention of the efflux of molecules after absorption, influencing the bioavailability and distribution of compounds in tissues. The high skin permeability of these compounds suggests the possibility of transdermal administration. The absence of toxicity in algae and non-mutagenicity in all 16 derivatives are indications of possible safety. Results of the analysis of carcinogenic activity between rats and mice indicate biological complexity, where only derivatives 56 and 77 did not show any carcinogenic activity. The presence of hydrogen acceptors and formation of covalent hydrogen bonds in compounds influences molecular interactions. Compounds 76 and 77 have LogP <5, indicating a hydrophilic character, while compounds 13, 15, 27, 58 and 76 have a molecular weight of less than 500 g/mol, indicating passivity to cross cell membranes. The diversity of results highlights the complexity of these compounds, encouraging future investigations with these innovative substances.