Determinação de alvo antimelanoma por modelagem in silico para derivado de beta-lapachona: integração de farmacologia de rede e docking molecular

Abstract

Cutaneous melanoma represents a continuous therapeutic challenge due to its aggressiveness and metastatic potential. In this context, β-lapachone, a natural naphthoquinone with proven antitumor activity, emerges as a promising candidate, although its clinical applicability is limited by pharmacokinetic obstacles. This work proposed the in silico development and characterization of an inclusion complex between a semisynthetic β-lapachone derivative containing aminopyrimidine (LP06A) and β-cyclodextrin (β-CD), evaluating its antimelanoma potential. The strategy integrated chemical synthesis, computational studies, and a network pharmacology approach. Molecular docking assays confirmed the formation of a stable inclusion complex (ΔG = -6.4 kcal/mol), with identification of multiple favorable conformations. Network pharmacology revealed simultaneous modulation of key targets for melanoma (MMP2, CDK2, and PARP-1), distributed across critical pathways such as Proteoglycans in cancer, Apoptosis, and Pathways in cancer. Studies with the PARP-1 enzyme confirmed that the LP06A derivative maintained competitive affinity with the reference drug Talazoparib. Predictive ADMET analysis demonstrated that although LP06A presents higher acute toxicity than native β-lapachone, it exhibits an improved organic safety profile and favorable metabolic characteristics. The results indicate that the inclusion complex with cyclodextrin was not favorable for drug incorporation; however, its antitumor potential remains promising, as evidenced by the network pharmacology analyses. These findings reinforce the need for complementary studies aimed at developing new formulation strategies capable of improving its pharmacokinetic profiles.