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Cancer cells can adapt to their surrounding microenvironment by upregulating glucose-regulated protein 78 kDa (GRP78) and vacuolar-type ATPase (V-ATPase) proteins to increase their proliferation and resilience to anticancer therapy. Therefore, targeting these proteins can obstruct cancer progression. A comprehensive computational study was conducted to investigate the inhibitory potential of four proton pump inhibitors (PPIs), dexlasnoprazole (DEX), esomeprazole (ESO), pantoprazole (PAN), and rabeprazole (RAB), against GRP78 and V-ATPase. Molecular docking revealed high-affinity scores for PPIs against both proteins. Moreover, molecular dynamics showed favorable root mean square deviation values for GRP78 and V-ATPase complexes, whereas root mean square fluctuations were high at the substrate-binding subdomains of GRP78 complexes and the α-helices of V-ATPase. Meanwhile, the radius of gyration and the surface-accessible surface area of the complexes were not significantly affected by ligand binding. Trajectory projections of the first two principal components showed similar motions of GRP78 structures and the fluctuating nature of V-ATPase structures, while the free-energy landscape revealed the thermodynamically favored GRP78-RAB and V-ATPase-DEX conformations. Furthermore, the binding free energy was −16.59 and −18.97 kcal/mol for GRP78-RAB and V-ATPase-DEX, respectively, indicating their stability. According to our findings, RAB and DEX are promising candidates for GRP78 and V-ATPase inhibition experiments, respectively.

Ranitidine is widely used to treat gastrointestinal conditions, but recent studies have revealed severe potential side effects, including a link to cancer. Therefore, this study aims to develop a new gastro-retentive formulation of ranitidine by utilizing the biocompatibility and biodegradability of Chitosan, along with the strength and hydrophilicity of polyvinyl alcohol (PVA). A chitosan/PVA/ranitidine hydrogel was created using the freeze-thaw method and evaluated for stability, ranitidine release behavior, and efficacy in treating ulcers in rats compared to a commercial formulation. The hydrogel demonstrates an average particle size of 69 nm, a polydispersity index of 0.344, and a zeta potential of + 38 mV. Transmission Electron Microscopy confirmed the spherical shape of the formulation, while X-ray diffraction verified its crystalline structure. Additionally, the study observed an impressive encapsulation efficiency of 98.66% ± 1.01 and a high drug content of 49.82% ± 1.29, as confirmed by Fourier transform infrared analysis. The prepared hydrogel controls the release of ranitidine over 12 h, with an average release of 87.98% ± 4.01%. The hydrogel exhibits minimal degradation over 15 days, greater thermal stability than ranitidine, and adequate stability in acidic gastric conditions. Furthermore, the cytotoxicity assay demonstrated that the hydrogel is biocompatible and promotes cell growth. The study discovered that the hydrogel formulation enhances the effects of ranitidine, particularly its antioxidant and anti-inflammatory properties. In vivo studies illustrated the hydrogel’s promising ulcer-healing properties, suggesting potential use in treating peptic ulcers. Hence, the chitosan/PVA hydrogel can be used as a possible drug delivery system for the sustained release of ranitidine.