Vol 31, No 5 (2024)

Background:Sesquiterpene lactones are secondary plant metabolites with a wide variety of biological activities. The process of lactone conjugation to other pharmacophores can increase the efficacy and specificity of the conjugated agent effect on molecular targets in various diseases, including brain pathologies. Derivatives of biogenic indoles, including neurotransmitter serotonin, are of considerable interest as potential pharmacophores. Most of these compounds have neurotropic activity and, therefore, can be used in the synthesis of new drugs with neuroprotective properties.

Aim:The aim of this experimental synthesis was to generate potential treatment agents for Alzheimer's disease using serotonin conjugated with natural sesquiterpene lactones.

Methods:Three novel compounds were obtained via the Michael reaction and used for biological testing. The obtained conjugates demonstrated complex neuroprotective activities. Serotonin conjugated to isoalantolactone exhibited strong antioxidant and mitoprotective activities.

Results:The agent was also found to inhibit β-site amyloid precursor protein cleaving enzyme 1 (BACE-1), prevent the aggregation of β-amyloid peptide 1-42, and protect SH-SY5Y neuroblastoma cells from neurotoxins such as glutamate and H2O2. In a transgenic animal model of Alzheimer's disease (5xFAD line), the conjugated agent restored declined cognitive functions and improved learning and memory.

Conclusion:In conclusion, the obtained results indicate that serotonin conjugates to sesquiterpene lactones are promising agents for the treatment of symptoms associated with Alzheimer's disease.

Cancer is a complex and debilitating disease that is one of the leading causes of death in the modern world. Computational methods have contributed to the successful design and development of several drugs. The recent advances in computational methodology, coupled with the avalanche of data being acquired through high throughput genomics, proteomics, and metabolomics, are likely to increase the contribution of computational methods toward the development of more effective treatments for cancer. Recent advances in the application of neural networks for the prediction of the native conformation of proteins have provided structural information regarding the complete human proteome. In addition, advances in machine learning and network pharmacology have provided novel methods for target identification and for the utilization of biological, pharmacological, and clinical databases for the design and development of drugs. This is a review of the key advances in computational methods that have the potential for application in the design and development of drugs for cancer.

Background:Epidermal growth factor receptor (EGFR/HER-1) and its role in tumor development and progression through the mechanism of tumor angiogenesis is prevalent in non-small lung cancer, head and neck cancer, cholangiocarcinoma & glioblastoma. Previous treatments targeting the oncogenic activity of EGFR's kinase domain have been hindered by acquired mutational resistance and side effects from existing drugs like erlotinib, highlighting the need for new EGFR inhibitors through structure- based drug designing.

Objective:The research aims to develop novel quinazoline derivatives through structure-based virtual screening, molecular docking, and molecular dynamics simulation to potentially interact with EGFR's kinase domain and impede tumor angiogenic phenomenon.

Methods:Quinazoline derivatives were retrieved and filtered from the PubChem database using structure- based virtual screening and the Lipinski rule of five drug-likeness studies. Molecular docking-based virtual screening methods and molecular dynamics simulation were then carried out to identify top leads.

Results:A total of 1000 quinazoline derivatives were retrieved, with 671 compounds possessing druglike properties after applying Lipinski filters. Further filtration using ADME and toxicity filters yielded 28 compounds with good pharmacokinetic profiles. Docking-based virtual screening identified seven compounds with better binding scores than the control drug, dacomitinib. After cross-checking binding scores, three top compounds QU524, QU571, and QU297 were selected for molecular dynamics simulation study of 100 ns interval using Desmond module of Schrodinger maestro to understand their conformational stability.

Conclusion:The research results showed that the selected quinazoline leads exhibited better binding affinity and conformational stability than the control drug, erlotinib. These compounds also had good pharmacokinetic and pharmacodynamic profiles and did not violate Lipinski’s rule of five limits. The findings suggest that these leads have the potential to target EGFR's kinase domain and inhibit the EGFR-associated phenomenon of tumor angiogenesis.

Background:Free radicals exist as unstable and highly reactive substances, occurring both in and outside the body. Free radicals are labeled as electron-hungry molecules formed from metabolism and endogenous burning of oxygen. They are transported in cells, upsetting the arrangement of molecules and instigating cellular injury. Hydroxyl radical (•OH) is one of the highly reactive free radicals, which damages the biomolecules in its close vicinity.

Methods:In the present study, DNA was modified by the hydroxyl radical generated via the Fenton reaction. The •OH-oxidized/-modified DNA (Ox-DNA) was characterized by UV-visible and fluorescence spectroscopy. Thermal denaturation was performed to reveal the susceptibility of modified DNA toward heat. The role of Ox-DNA was also established in probing the presence of autoantibodies against Ox-DNA in the sera of cancer patients by direct binding ELISA. The specificity of autoantibodies was also checked by inhibition ELISA.

Results:In biophysical characterization, an increase in hyperchromicity and relative reduction of fluorescence intensity for Ox-DNA was reported compared to the native DNA analog. A thermal denaturation study revealed that Ox-DNA was highly susceptible to heat in comparison to the native conformers. The direct binding ELISA showed the prevalence of autoantibodies from cancer patient sera separated for immunoassay detection against the Ox-DNA. The generated autoantibodies against the Ox-DNA were detected as highly specific against bladder, head, neck, and lung cancer, which was further confirmed by the inhibition ELISA for the serum and IgG antibodies.

Conclusion:The generated neoepitopes on DNA molecules are recognized as nonself by the immune system, which leads to the formation of autoantibodies in cancer patients. Therefore, our study confirmed that oxidative stress plays a role in the structural perturbation of DNA and makes it immunogenic.