Journal of Molecular Recognition

Nanohydrogel of Curcumin/Berberine Co‐Crystals Induces Apoptosis via Dual Covalent/Noncovalent Inhibition of Caspases in Endometrial Cancer Cell Lines: The Synergy Between Pharmacokinetics and Pharmacodynamics

ABSTRACTEndometrial cancer remains a significant therapeutic challenge due to drug resistance and heterogeneity. This study leverages the synergistic potential of curcumin (CUR) and berberine (BBR) co‐crystals encapsulated in a nanohydrogel to address these challenges through a pharmacokinetically and pharmacodynamically targeted therapeutic strategy. The nanohydrogel formulation significantly improves the solubility, stability, and bioavailability of CUR/BBR co‐crystals, optimizing their therapeutic delivery and sustained release under physiological and tumor microenvironment conditions. On the other hand, the dual inhibitory mechanism of CUR and BBR, with CUR covalently binding to the active site of caspase‐3 and BBR non‐covalently targeting the allosteric site, achieves enhanced apoptotic activity by disrupting both the catalytic and conformational functions of caspase‐3. In vitro cytotoxicity assays demonstrate remarkable efficacy of the CUR/BBR nanohydrogel, achieving an IC50 of 12.36 μg/mL against HEC‐59 endometrial cancer cells, significantly outperforming the individual components and the standard drug Camptothecin (IC50: 17.27 μg/mL). Caspase‐3/7 assays confirm enhanced apoptosis induction for the nanohydrogel formulation compared to co‐crystals alone and Camptothecin. Molecular dynamics simulations and binding free energy analyses further validate the synergistic interaction of CUR and BBR in their dual binding mode. This study introduces a novel therapeutic approach by enhancing drug delivery and dual targeting mechanisms, demonstrating the potential of CUR‐BBR nanohydrogel as a robust therapy for EC. This strategy offers a promising platform for addressing drug resistance and improving outcomes in endometrial cancer therapy.

Systematic inhibitor selectivity between PARP1 and PARP2 enzymes: Molecular implications for ovarian cancer personalized therapy

AbstractHuman poly(ADP‐ribose) polymerases (PARPs) are a class of nuclear enzymes involved in the pathogenesis of diverse gynecologic tumors. The PARP1 and PARP2 are the two most documented members in PARP family, which have been approved as the druggable targets of ovarian and cervical cancers. Selective targeting of the two enzymes with small‐molecule inhibitors is a great challenge due to the high conservation in catalytic domain and active site. Here, we investigate the systematic selectivity profile of sophisticated PARP inhibitors between the two enzymes. Computational methods are used to model/optimize the complex structures of inhibitor ligands with PARP1/2 catalytic domains and then to estimate the theoretical Fenzymatic assays exhibit a good consistence with theoretical selectivity over six tested inhibitor samples (rc2 = 0.857). It is revealed that the inhibitor selectivity is conferred from the exquisite difference in the residue composition and structural architecture of both the local activity sites and the whole catalytic domains of the two enzymes. In particular, the TMZ50 and ME0328 show strong selectivity between PARP1 and PARP2, but only the former has a potent activity on the two enzymes, whereas the latter can only inhibit the enzymes moderately. These compounds can be considered as potential lead molecular entities to develop new specific PARP‐selective inhibitor drugs for personalized therapy combating gynecologic cancers.