Endosomal entrapment significantly limits the efficacy of drug delivery systems. This study investigates sodium oleate-modified liposomes (SO-Lipo) as an innovative strategy to enhance endosomal escape and improve cytosolic delivery in 4T1 triple-negative breast cancer cells. We aimed to elucidate the mechanistic role of sodium oleate in promoting endosomal escape and compared the performance of SO-Lipo with unmodified liposomes (Unmodified-Lipo) and Aurein 1.2-modified liposomes (AUR-Lipo). Liposomes were prepared using the thin-film hydration method, resulting in Unmodified-Lipo, SO-Lipo, and AUR-Lipo formulations. The particle sizes were 102.2 ± 3.30 nm for Unmodified-Lipo, 109.6 ± 7.65 nm for SO-Lipo, and 151.9 ± 5.88 nm for AUR-Lipo, with polydispersity indices below 0.25, indicating uniform size distribution. Endosomal escape efficiency was evaluated through confocal microscopy by measuring the colocalization of labeled liposomes with lysosomal markers, quantified using Pearson’s correlation coefficient. Lipid mixing assays assessed the potential fusogenic effect, and molecular dynamics (MD) simulations explored the interactions of protonated sodium oleate (SO) with the endosomal membrane. Results demonstrated that SO-Lipo exhibited superior endosomal escape compared to Unmodified-Lipo, as evidenced by reduced colocalization with lysosomal markers, and achieved comparable efficacy to AUR-Lipo with lower cytotoxicity. Lipid mixing assays confirmed the potential fusogenic effect of SO with endosomal membrane models. MD simulations revealed that under acidic endosomal conditions, SO is protonated to oleic acid, which integrates into the membrane, enhancing fluidity and promoting fusion events essential for cytosolic release. SO-Lipo enhance endosomal escape through a fusogenic mechanism, facilitating cytosolic delivery with reduced cytotoxicity. This approach offers a safer and more effective option for targeted drug delivery applications.

Five known porphyrins, 5,10,15,20-tetrakis(p-tolyl)porphyrin (TTP), 5,10,15,20-tetrakis(p-bromophenyl)porphyrin (TBrPP), 5,10,15,20-tetrakis(p-aminophenyl)porphyrin (TAPP), 5,10,15-tris(tolyl)-20-mono(p-nitrophenyl)porphyrin (TrTMNP), 5,10,15-tris(tolyl)-20-mono(p-aminophenyl)porphyrin (TrTMAP), and three novel porphyrin derivatives, 5,15-di-[bis(3,4-ethylcarboxymethylenoxy)phenyl]-10,20-di(p-tolyl)porphyrin (DBECPDTP), 5,10-di-[bis(3,4-ethylcarboxymethylenoxy)phenyl]-15,20-di-(methylpyrazole-4-yl)porphyrin (cDBECPDPzP), 5,15-di-[bis(3,4-ethylcarboxymethylenoxy)phenyl]-10,20-di-(methylpyrazole-4-yl)porphyrin (DBECPDPzP), were used to study their interaction with protein targets (in silico study), and were synthesized. Their cytotoxic activities against cancer cell lines were tested using 3-(4,5-dimetiltiazol-2-il)-2,5-difeniltetrazolium bromide (MTT) assay. The interaction of porphyrin derivatives with carbonic anhydrase IX (CAIX) and REV-ERBβ proteins were studied by molecular docking and molecular dynamic simulation. In silico study results reveal that DBECPDPzP and TrTMNP showed the highest binding interaction with REV- ERBβ and CAIX, respectively, and both complexes of DBECPDPzP-REV-ERBβ and TrTMNP-CAIX showed good and comparable stability during molecular dynamic simulation. The studied porphyrins have selective growth inhibition activities against tested cancer cells and are categorized as marginally active compounds based on their IC₅₀.

Nuclear receptor REV-ERBβ is an overexpressed oncoprotein that has been used as a target for cancer treatment. The metal-complex nature of its ligand, iron protoporphyrin IX (Heme), enables the REV-ERBβ to be used for multiple therapeutic modalities as a photonuclease, a photosensitizer, or a fluorescence imaging agent. The replacement of iron with cobalt as the metal center of protoporphyrin IX changes the ligand from an agonist to an antagonist of REV-ERBβ. The mechanism behind that phenomenon is still unclear, despite the availability of crystal structures of REV-ERBβ in complex with Heme and cobalt protoporphyrin IX (CoPP). This study used molecular dynamic simulations to compare the effects of REV-ERBβ binding to Heme and CoPP, respectively. The initial poses of Heme and CoPP in complex with agonist and antagonist forms of REV-ERBβ were predicted using molecular docking. The binding energies of each ligand were calculated using the MM/PBSA method. The computed binding affinity of Heme to REV-ERBβ was stronger than that of CoPP, in agreement with experimental results. CoPP altered the conformation of the ligand-binding site of REV-ERBβ, disrupting the binding site for nuclear receptor corepressor, which is required for REV-ERBβ to regulate the transcription of downstream target genes. Those results suggest that a subtle change in the metal center of porphyrin can change the behavior of porphyrin in cancer cell signaling. Therefore, modification of porphyrin-based agents for cancer therapy should be conducted carefully to avoid triggering unfavorable effects.

Melanoma is the most aggressive type of skin cancer. Metastatic melanoma is extremely difficult to treat with current therapy methods such as surgery. On the other hand, it is a good opportunity to develop a radiopharmaceutical using a radionuclide such as technetium (Tc) for diagnostic and rhenium (Re) for therapeutic purposes. T3,4BCPP has been be used as a radioimaging agent for melanoma cancers experimentally. The aim of the present research was to design new imidazolylporphyrin derivatives with better selectivity and higher affinity than those of T3,4BCPP by molecular modeling. Eight types of Re- and Tc-labeled imidazolylporphyrins were docked to Fibroblast Growth Factor Receptor 1 (FGFR1, PDB ID: 5AM6) using AutoDock 4.2. FGFR1 was simulated by molecular dynamic (MD) simulation for 30 ns using NAMD 2.10 at 37 °C. The obtained conformations were then applied in a molecular docking simulation. Dovitinib (natural ligand of FGFR1), Re- and Tc-T3,4BCPP were used as references. The MD simulation resulted in an RMSD of 3.8 Å. From all the studied imidazolylporphyrin derivatives, Tc-cD3,4BCPMIP and Re-cD3,4BCPIP had the best docking parameter. Tc-cD3,4BCPMIP had a free binding energy of −4.06 kcal/mol, while that of Re-cD3,4BCPIP was −4.35 kcal/mol. It is concluded that cD3,4BCPMIP and cD3,4BCPIP are two potential candidate ligands for a melanoma radiopharmaceutical.

This study aims to determine the antiobesity activity of Calophyllum soulattri leaves extract (CSLE) on high fat diet-fed rats (HFD) and to predict the molecular docking and pharmacokinetics of selected compounds of Calophyllum soulattri to fat mass and obesity-associated protein (FTO). Daily body weight, organ, carcass fat (renal and anal), body mass index, total cholesterol, and total triglyceride levels were observed after CSLE was given orally for 50 days. Furthermore, body mass index of a CSLE dose of 50 mg/kgbw, 100 mg/kgbw and orlistat (120 mg/kgbw) group are 0.68, 0.57 and 0.52, respectively. The total body weight of the CLSE dose of 100 mg/kgbw group showed the lowest percentage change, followed by a CLSE dose of 50 mg/kgbw compared to the normal and positive control group. The carcass fat index of CSLE dose of 100 mg/kgbw was not significantly different from orlistat, which was in line with its total cholesterol level and triglyceride (p < 0.05). The binding affinity of selected compounds from Calophyllum soulattri (friedelin, caloxanthone B, macluraxanthone, stigmasterol, trapezifolixanthone, dombakinaxanthone, and brasixanthone B) to FTO are –8.27, –9.74, –8.48, –9.34, –8.85, –8.68 and –9.39 kcal/mol, which are better than that of orlistat at –4.80 kcal/mol. The molecular dynamics simulation showed that the interaction between Caloxanthone B compounds and obesity receptors was relatively stable. Lipinski’s rule determined the absorption percentage of all compounds above 90% with good drug-likeness. The results showed the potential of CSLE as an antiobesity drug candidate.

Laportea decumana (Roxb.) Wedd., known as itchy leaves, is traditionally used for pain relief due to its bioactive compounds. However, previous studies were limited by resource-intensive in vivo methods and a lack of mechanistic insights into cyclooxygenase (COX)-1 and COX-2 binding. The aim of this study was to identify compounds in the n-hexane and ethyl acetate extracts of L. decumana with potential as COX-1 and COX-2 inhibitors and to predict their binding affinity and stability within the binding pocket through molecular dynamics simulations. Leaves collected from Arso, Keerom Regency, Papua, Indonesia, were dried, sieved into simplicia, and macerated with n-hexane to obtain a n-hexane extract. The residual simplicia was further macerated with ethyl acetate to produce an ethyl acetate extract. N-hexane extract compounds were analyzed by gas chromatography-mass spectrometry (GC-MS), and ethyl acetate extract compounds by liquid chromatography-mass spectrometry (LC-MS). Identified chemicals were used in in silico evaluations targeting COX-1 and COX-2. This study identified ten compounds with high performance in docking analysis, which were further evaluated by molecular dynamics. The n-hexane extract contained 31 compounds, while the ethyl acetate extract contained 27. Among these, 4,8,12,16-tetramethylheptadecan-4-olide from the n-hexane extract demonstrated the strongest affinity for both COX-1 and COX-2, with binding free energies of -41.62±1.03 kcal/mol and -33.05±0.11 kcal/mol, respectively. Its interactions were comparable to those of native ligands, with superior binding free energy. In the ethyl acetate extract, pseudosantonim demonstrated the highest affinity for COX-1 (-24.41±1.32 kcal/mol), while arteamisinine showed strong potential as a COX-2 inhibitor (-23.53±0.30 kcal/mol). In conclusion, 4,8,12,16-tetramethylheptadecan-4-olide was the most potent COX-1 and COX-2 inhibitor, pseudosantonim was the most effective COX-1 inhibitor, and arteamisinine demonstrated COX-2 inhibitory potential. Further validation through in vitro or in vivo studies is recommended.