Reposicionamento de fármacos por docking molecular direcionado às proteínas PNMA3 e RASSF2 associadas à resistência à quimioradioterapia no câncer de colo uterino

Abstract

Cervical cancer (CC) remains one of the most lethal malignancies among women, particularly in low- and middle-income countries. Its primary etiology is associated with persistent infection by oncogenic human papillomavirus (HPV) genotypes. Worsening this scenario, chemoradiotherapy resistance in certain patients remains a significant clinical challenge. Previous transcriptomic studies identified the overexpression of RASSF2 and PNMA3 genes in non-responsive patients, raising the hypothesis that PNMA3 might disrupt the association between RASSF2 and MST1/MST2 kinases, which are critical components of the Hippo apoptotic pathway. This study aimed to investigate, through structural bioinformatics approaches, whether PNMA3 and RASSF2 interact, and if so, to identify the interaction site and assess its impact on Hippo pathway activation. Rational drug repositioning was also explored as a strategy to modulate or block this interaction. Three-dimensional models of PNMA3 and RASSF2 were obtained from public databases, and a drug library was generated through systematic filtering of the ChEMBL database. Protein–protein and protein–ligand docking analyses, followed by molecular dynamics simulations, were performed using the MOE software, with subsequent data processing in R. The results indicated that PNMA3 forms a strong and stable interaction with RASSF2 at the SARAH domain, potentially impairing apoptotic signaling. Virtual screening revealed compounds with differential selectivity. Among the candidates, Nebivolol stood out as the most promising, exhibiting high affinity for PNMA3 (S = –9.42 kcal/mol) and no significant interaction with RASSF2, supporting its potential to selectively disrupt this pathological interaction. In this context, rational drug repositioning emerges as a promising strategy to design alternative therapeutic approaches to overcome resistance in cervical cancer.