Jumina Jumina

Fatty acid synthase (FASN) is overexpressed in many cancers and has therefore emerged as a potential target for anticancer drug development, particularly through inhibition of the thioesterase domain. In this study, 21 N-aryl oleamide derivatives were rationally designed and screened via molecular docking against the thioesterase (TE) domain of FASN. N-phenyloleamide (OA2) and N-(o-tolyl)oleamide (OA3) emerged as the top candidates and were further evaluated in their epoxidized forms: 8-(3-octyloxiran-2-yl)-N-phenyloctanamide (EOA2) and 8-(3-octyloxiran-2-yl)-N-(o-tolyl) octanamide (EOA3). The epoxide derivatives exhibited enhanced binding affinities (OA2 = − 5.49, OA3 = − 5.36, EOA2 = − 5.85, and EOA3 = − 5.84 kcal/mol), with EOA2 showing interactions with the catalytic triad (Ser2308, Asp2338, His2481), suggesting a favorable binding orientation. The selected compounds (OA2, OA3, EOA2, and EOA3) were synthesized and evaluated for cytotoxic activity. EOA2 demonstrated the most potent activity against HeLa cells (IC₅₀ = 6.16 µg/mL) and showed notable selectivity over normal Vero cells. Molecular dynamics simulations over 300 ns confirmed stable binding, as evidenced by consistent root mean square deviation, root mean square fluctuation, radius of gyration, solvent-accessible surface area, and hydrogen-bond profiles. Molecular mechanics Poisson-Boltzmann surface area analysis showed a favorable binding free energy of − 27.62 ± 2.44 kcal/mol, indicating that hydrophobic and electrostatic interactions stabilize the complex. Protein secondary structure and Ramachandran analyses further confirmed preservation of protein structural integrity throughout the simulation, while ADMET predictions indicated acceptable drug-likeness. These findings suggest EOA2 as a promising anticancer lead compound with cytotoxic activity against HeLa cells and good selectivity toward cancer cells.

The global rise of antibiotic-resistant bacteria poses a critical health challenge, necessitating the discovery of new antibacterial agents. In this study, three hydroxyxanthone derivatives, 1,5-dihydroxyxanthone (HX1), 1,6-dihydroxyxanthone (HX2), and 1,7-dihydroxyxanthone (HX3) were synthesized in 3.5, 38.2, and 17.54% yields, respectively. In vitro assays revealed that all compounds were inactive against Escherichia coli (MIC > 1000 µg/mL) but exhibited potent inhibition of Pseudomonas aeruginosa (MIC 15.62 µg/mL). Compounds HX1 and HX3 also demonstrated strong activity against Staphylococcus aureus and Bacillus subtilis (MICs of 15.62 µg/mL), while HX2 showed moderate activity (MIC of 31.25 µg/mL). Molecular docking indicated favorable binding energies (–6.23 to –6.68 kcal/mol) toward DHFR from E. coli and S. aureus, surpassing those of trimethoprim and tetracycline. Molecular dynamics simulations confirmed stable ligand–protein interactions, and ADMET analyses potential drug-likeness and pharmacokinetic profiles. Overall, HX1 and HX3 emerge as promising lead scaffolds for the development of novel DHFR-targeted antibacterial agents against both Gram-positive and Gram-negative pathogens.

Dioleate and trioleate epoxides were successfully obtained from palm oil through several steps and evaluated as anticancer agent potential via in vitro assays and studies of their binding to the FASN protein. At first, fatty acid methyl esters (FAMEs) were isolated through the transesterification reaction from palm oil. Next, the methyl oleate from FAME was purified through urea inclusion method and then hydrolyzed into oleic acid. The oleic acid was further reacted with 1,2-propanediol and glycerol to produce 1,2-propanеdiol dioleate (dioleate) and glyceryl-1,2,3-trioleate (trioleate) derivatives, respectively. The dioleate and trioleate compounds were epoxidized with performic acid reagent to yield dioleate and trioleate epoxides, respectively. Trioleate epoxide generated a more potent anticancer activity against T47D and WiDr cancer cells with IC50 values of 27.40 and 32.41 mg L^{-1} , respectively. In comparison, the IC50 values of dioleate epoxide against T47D and WiDr cancer cells are 35.66 and 38.25 mg L^{-1} . Trioleate epoxide and dioleate epoxide were non-toxic for normal cells with selectivity index values of 9.19-10.87 and 7.60-8.16, respectively. The molecular docking showed that dioleate and trioleate epoxides could inhibit the function of the FASN enzyme with binding affinity values of -27.11 and -27.61 kJ mol^{-1} , respectively.

Cancer and malaria are two fatal diseases found in Indonesia over the past several years. Therefore, researchers are trying their best to find new anticancer and antimalarial agents. In the present work, we evaluated five xanthone-fatty acid hybrids, i.e., xanthyl laurate (XL), xanthyl myristate (XM), xanthyl palmitate (XP), xanthyl stearate (XS), and xanthyl oleate (XO), as novel anticancer and antimalarial agents. The cytotoxicity assay towards NIH3T3 reveals that xanthone-fatty acid hybrids showed a selectivity index up to 282.08, demonstrating their non-toxic profile. The MTT assay found that XO yielded stronger breast anticancer activity than doxorubicin as the positive control. All xanthone-fatty acid hybrids exhibited moderate antimalarial activity with IC50 values of 24.24–87.57 µM, lower than that of chloroquine diphosphate as the positive control (4.26 µM). As the best anticancer agent for breast cancer, the mode of action of XO was further studied by computational studies. The molecular docking results showed the binding energy against the HER2 protein was −45.73 kJ/mol through a hydrogen bond with Lys753. This hydrogen bond remained stable until the end of the molecular dynamics simulations for 100 ns. These findings highlight the potential application of XO as a new drug candidate for breast cancer treatment.

A comprehensive QSAR analysis, in conjunction with molecular docking, molecular dynamics simulations, MM-PBSA binding energy estimations, and ADMET profiling, was conducted to facilitate the development of novel anticancer agents based on hydroxyxanthone derivatives. Molecular and electronic descriptors were calculated using the DFT method with the 3-21G basis set. The best QSAR model identified several descriptors that significantly influence anticancer activity, including the atomic charges at positions C1, C3, C4a, and C7, as well as the highest occupied molecular orbital (HOMO), surface area (SA), molecular volume (VOL), and molecular weight (MW). This model was used to design novel hydroxyxanthone derivatives (X27 to X47). The docking result showed that compounds 7-bromo-3-hydroxy-1-(methylamino)-9H-xanthen-9-one (X43), 6-hydroxy-8-(methylamino)-9-oxo-9H-xanthene-2-carbonitrile (X44), and 3-hydroxy-7-mercapto-1-(methylamino)-9H-xanthen-9-one (X45) had stronger binding energy values than gefitinib as a native ligand. Gefitinib had a binding energy of -6.84 kcal/mol, while those compounds had values of -6.92, -7.12, and -6.92 kcal/mol, respectively. In a molecular dynamics simulation of 100 ns, compounds X43, X44, and X45 exhibited stability comparable to that of gefitinib against the EGFR protein. Additionally, the binding energy MM-PBSA of compound X43 was the lowest (-29.18 kcal/mol), followed by X44 (-27.11 kcal/mol), gefitinib (-26.06 kcal/mol), and X45 (-25.21 kcal/mol). Furthermore, these compounds met Lipinski's rule parameters and the minimal standard parameters in terms of ADMET characteristics, as predicted by physicochemical properties. In conclusion, compounds X43, X44, and X45 are potential anticancer agents for MDA-MB-231 breast cancer cells.

Nowadays, the discovery of active anticancer agents has become urgent research due to the high mortality of cancer patients. Herein, we designed some chlorinated hydroxyxanthones to examine the effect of the presence and position of the chloro group on the inhibitory activity of the PDGFR. The molecular docking reveals that 5-chloro-1-hydroxyxanthone (5Cl) exhibited the strongest binding energy (−7.95 kcal/mol) against PDGFR. The molecular dynamic simulation results demonstrated a high stability of the 5Cl-PDGFR complex as revealed by the average RMSD (0.37 ± 0.15 Å) and RMSF (0.83 ± 0.64 Å), and two maintained hydrogen bonds with Cys673 through hydroxyl and carbonyl groups with an average bond distance of 2.29 ± 0.54 and 2.49 ± 0.64 Å, respectively. Afterward, 5Cl and other chlorinated hydroxyxanthones were synthesized in a one-pot reaction with a 15.1–25.2% yield. From the in vitro experiment, 5Cl exhibited the lowest IC₅₀ value of 3.065–3.785 µM against breast (MCF-7), cervical (HeLa), and colorectal (WiDr) cancer cells. Furthermore, 5Cl exhibited the highest selectivity index (8.737–10.79), showing that 5Cl is not toxic to the Vero normal cells, which agreed with the ADMET predictions. These findings highlight the potential application of 5Cl as a new anticancer agent that will be investigated further and developed in the future.

Background: Epidermal growth factor receptor tyrosine kinase [EGFR TK] is a primary target for inhibiting cellular signal transduction in several types of cancer. Numerous EGFR TK inhibitors have been developed and approved as standard therapy for cancer management. However, the development of drug resistance and significant adverse effects have encouraged the search for alternative EGFR TK inhibitors. Objective: This study attempted to identify 2,4-diaryl-6-styrylpyridine derivatives as alternative orthosteric-allosteric EGFR TK inhibitors through molecular docking, molecular dynamic simulation, binding free energy calculation, and pharmacokinetic properties analysis. Methods: Two series of 2,4-diaryl-6-styrylpyridine derivatives were docked in orthosteric and allosteric sites of EGFR TK. Docking results were validated through molecular dynamic simulation and binding free energy calculation using YASARA Structure. Pharmacokinetic properties were analyzed using web-based free servers SwissADME and ADMETLab 3.0. Results: The molecular docking studies revealed relatively strong affinity, with binding energy ranging from -10.3 to -12.2 kcal/mol in the orthosteric site and from -8.3 to -10.9 kcal/mol in the allosteric site of EGFR TK. The proposed ligand complexes with the highest binding energy and proper hydrogen bonds showed comparable stability and binding free energy than native ligand complexes. The pharmacokinetic properties of the proposed ligands indicated relatively poor characteristics due to relatively high lipophilicity and certain toxicophores. Conclusion: This study identified NASP06 and NASP01 as the most stable orthosteric and allosteric inhibitors of EGFR TK, respectively. These findings revealed a novel class of EGFR TK inhibitors capable of interacting with both orthosteric and allosteric sites.

Breast cancer is one of the deathliest cancer diseases for women, with high mortality cases. Since breast cancer cells overexpressed HER2 receptors, a computerized structure-based screening was conducted to identify potential HER2 inhibitors as an anti-breast cancer agent. This method can investigate the potency of proposed compounds as potential protein inhibitors. Researchers were interested in studying some synthetic macromolecules, i.e., allyl-modified calix[4]resorcinarenes, through in silico studies as HER2 inhibitors using molecular docking studies. Prospective protein-ligand complexes for HER2 inhibition were further investigated by molecular dynamics simulations for 200 ns on different binding pockets. The allyloxycalix[4]resorcinarene derivative (5A) was identified as the most potential HER2 inhibitor through a computational approach, including molecular docking studies and molecular dynamics simulations. The HER2-5A complex was relatively stable during the 200 ns molecular dynamics run. In addition, the hydrogen bonds formed between blind docking and molecular dynamics simulations are almost unchanged for the HER2-5A complex. The HER2-5A formed with two crucial amino acid residues, i.e., Asp845 and Asn850. Moreover, the data of the molecular dynamics simulations of compounds 5A and 2A demonstrate the stability of both complexes in different binding sites of HER2. These computational results are preliminary data for further synthesis and in vitro evaluation.

Malaria is an endemic disease in Indonesia caused by infection from the Plasmodium parasite. Recently, antimalarial resistance significantly contributed to the decline in the cure rate of malaria sufferers. In this work, three calix[4]resorcinarenes have been synthesized from 2-methylresorcinol and different benzaldehyde derivatives, i.e., 4-chlorobenzaldehyde, 4-methoxybenzaldehyde, and 4-dimethylaminobenzaldehyde through the one-pot synthesis procedure. The calix[4]resorcinarenes synthesis was done through a cyclo-condensation reaction by using HCl 37% as the catalyst and ethanol as the solvent in an one-pot reaction. The structures of the synthesized products were confirmed using Fourier transform infrared, proton-nuclear magnetic resonance, and liquid chromatography-mass spectrometry techniques. The antimalarial activity assay was evaluated against the Plasmodium falciparum FCR-3 strain through an in vitro study. Three synthesized compounds, i.e., C-4-chlorophenylcalix[4]-2-methylresorcinarene, C-4-methoxyphenylcalix[4]-2-methylresorcinarene and C-4-dimethylaminophenylcalix[4]-2-methylresorcinarene have been successfully synthesized in up to 97% yield. The C-4-chlorophenylcalix[4]-2-methylresorcinerene exhibited the most potent antimalarial activity with a half-maximal inhibitory concentration (IC50) value of 2.66 µM against P. falciparum FCR-3 while the C-4-methoxyphenylcalix[4]-2-methylresorcinarene and C-4-dimethylaminophenylcalix[4]-2-methylresorcinarene gave the IC50 values of 23.63 and 13.82 µM, respectively. From the results, it could be concluded that the antimalarial activity of calix[4]-2-methylresorcinarenes was influenced by the type of substituent of aromatic rings at the para position.