Vol 18, No 3 (2024)

Background:Diabetic retinopathy (DR) is the leading cause of vision loss in diabetic patients. Currently, the treatment involves the use of glucocorticoids or a VEGF antagonist, which are \"off-label\" at present. However, the conventional method of drug discovery and development is a time-consuming process that requires more than a decade of meticulous research and huge financial support. While there are a few effective small organic molecules against DR that were identified many years ago, nutraceuticals - naturally available functional foods containing vitamins, antioxidants, minerals, fatty acids, and amino acids - can also help delay the progression of some diseases.

Methods:In this study, 43 phytochemical constituents from four medicinal plants were tested for their binding affinity to the influential VEGFR2 target of diabetic retinopathy. The study used a computational approach, in silico molecular docking study, structure-based drug design approach, MSD (Molecular Dynamic Simulation analysis), in silico ADME(T) studies.

Results:The study reported that all phytochemical constituents displayed good to the highest binding affinity than the standard ruboxistaurin. Six phytochemical constituents, namely terchebulin, pedunculagin, punicalagin, punicalin, casuariniane, and chebulagic acid, exhibited equipotent to higher activity than the standard. These constituents displayed conventional hydrogen bonds, pialkyl, and pi-cation interactions to achieve their high binding affinity. The highest binding scores were chosen for analysis using MSD, ensuring stability of the ligand-protein complex. Pharmacodynamic and pharmacokinetic properties were evaluated, and their safety profile was validated.

Conclusion:This in silico screening study suggests that active phytomolecules present in medicinal plants may inhibit the VEGFR2 target. The best-docked compounds, possessing drug-like properties, can be used to develop potential inhibitors against DR or to mitigate its severity.

Background:Phosphorylated α-Synuclein (α-Syn) is present in relatively small levels in normal human brains, but nearly all of the α-Syn in the Lewy bodies (LBs) that collect in the nigrostriatal region in the brain of Parkinson's disease patients is phosphorylated on serine 129 (pS129). Earlier studies suggested that mimicking phosphorylation at S129 may have an inhibitory effect on α-Syn aggregation and thus control α-Syn neuropathology. Although phosphorylation at S129 is associated with α-Syn inclusion in synucleinopathies, the mechanisms by which this post-translational modification (PTM) influences aggregation and contributes to LB illness in the brain are yet to be understood.

Objective:This research aims to study the effect of phosphorylation (pS129) on the conformational dynamics of membrane-bound α-Syn using Molecular Dynamics (MD) simulations.

Method:Using MD simulations, this computational study has demonstrated the effect of PTM on the conformational dynamics of pS129 α-Syn and its lipid membrane association. To better understand the impact of pS129 on the aggregation of the α-Syn structure monomer with recent atomic details, we have examined the MD trajectories, conducted a salt-bridge interaction study, Principal Component Analysis (PCA), and intra and inter-molecular hydrogen bond analysis.

Results:The conformational structure of pS129 α-Syn was observed from the MD trajectory analysis to be stable throughout the simulation, with higher compactness and reduced flexibility. The stability of the structure of pS129 α-Syn was also evaluated by 2-D and 3-D principal component analysis followed by a free energy landscape plot showing the global minima. The conformational snapshots and Ramachandran plot showed the absence of α-strands in the α-Syn's Non-Amyloid Component Region (NAC) (71–82), which is necessary for aggregate formation.

Conclusion:Further, the intermolecular hydrogen bonds analysis indicates that the NAC region is not embedded into the lipid bilayer and has limited association with the other regions of the protein. Our findings reveal salient features of pS129 modifications that inhibit α-Syn aggregation.

Background:Chalcones have been demonstrated to possess numerous therapeutic qualities in recent years, such as antibacterial, antiviral, anti-ulcerative, antioxidant, antiinflammatory, antihyperglycemic, antimalarial, antitubercular, analgesic, antiplatelet, and anticancer activities.

Objective:To explore the synthesis, docking, and therapeutic characteristics of chalcones as antibacterial and anthelmintic compounds.

Methods:The chalcone derivatives (3a-3k) and (6l-6v) were synthesized via two selective different reactions, based on the Claisen-Schmidt reaction. All synthesized compounds were evaluated for their antibacterial activity using an in vitro cup-plate method, and their anthelmintic activity was assessed using an in vitro earthworm paralysis and death assay. To validate these findings, conducted molecular docking experiments between the dihydrofolate reductase receptor (PDB ID: 4LAE) and the synthesised compounds (3a-3k) and (6l-6v) to determine catalytic interactions

Results:Compound 6(n) exhibited the greatest efficacy in biological in vitro activity against S. aureus compared to all other compounds examined. Compound 6(o) exhibited substantial efficacy against P. posthuma and E. coli. Emphasizing these findings, the compounds 3(a), 3(g), 3(i), 6(n), and 6(o) demonstrated hydrogen bond interactions with certain amino acid residues of the receptor, including THR 122, ASN 18, ASN19, GLN 96, SER 50, and ALA 8, during molecular docking.

Conclusion:The study results showed that the synthesised derivative (E)-1-(napthalen-2-yl)-3-(4- (trifluoromethoxy)phenyl)prop-2-en-1-one 6(n) had beneficial antibacterial properties against S. aureus, while derivative (E)-1-(Napthalen-2-yl)-3-(4-trifluoromethyl)phenyl)prop-2-en-1-one 6(o) exhibited antibacterial activity against E. coli and anthlelmintic activity against P. posthuma.