Toxicologia e farmacologia da Biflorina: uma abordagem in silico

Abstract

The discovery of new drugs increasingly uses in silico methods, which have proven to be an important tool in the early stages of research for the identification, selection and optimization of molecules with therapeutic potential. Studies carried out with biflorin point to this ortho-naphthoquinone as a promising molecule in the research of drugs for the treatment of cancer, since its cytotoxic activity was evidenced on tumor cells of different types of cancer, both in vitro and in vivo. In this context, this study correlated the physicochemical properties, the toxicological and pharmacological potential of biflorin described in the literature with the in silico findings. Furthermore, the interaction of biflorin with the following biological targets was investigated: AKT-1, BRAF, EGFR, topoisomerase I, topoisomerase IIα and IIβ. To evaluate the physicochemical and pharmacokinetic parameters of biflorin, the software SwissADME® and PreADMET®, respectively, were used. The evaluation of toxicological parameters related to carcinogenicity, mutagenicity, genotoxicity, hepatotoxicity and irritant effects was performed using PreADMET®, Osiris Property Explorer®, admetSAR®, ProTox-II® and Lazar Toxicity Predictions® software. The interaction of biflorin with the proposed biological targets was investigated through molecular anchorage using Autodock Vina® software. The available literature showed relevant in vitro and in vivo studies performed with biflorin, however, no studies involving in silico methodologies were found. Biflorin analyzes pointed out physicochemical properties that make it eligible for drug development and the results of the in silico toxicological analysis demonstrated that biflorin is a safe substance. Molecular anchoring analysis of the interaction of biflorin with biological targets indicated that the inhibition of AKT-1 by biflorin does not occur by direct interaction with this enzyme, but by interaction with N-cadherin, that the inhibition of EGFR expression occurs by the interaction of biflorin with the enzymes involved in this pathway, and not by direct interaction with this target, and that the induction of cell death in melanoma cells expressing BRAF is possibly caused by binding with other enzymes involved in the cell cycle and not by direct interaction with this target. Regarding topoisomerases, the interaction of biflorin with this enzyme in silico was observed, but not with topoisomerase type II, which indicates that more robust studies need to be carried out with this target in order to elucidate the real mechanism of this interaction. All these compiled data can contribute to the study of the mechanism of action of this promising molecule with anticancer potential, one of the biggest challenges in therapy today.