Current Issue : April-June Volume : 2024 Issue Number : 2 Articles : 5 Articles
In response to the urgent demand for innovative antibiotics, theoretical investigations have been employed to design novel analogs. Because griseofulvin is a potential antibacterial agent, we have designed novel derivatives of griseofulvin to enhance its antibacterial efficacy and to evaluate their interactions with bacterial targets using in silico analysis. The results of this study reveal that the newly designed derivatives displayed the most robust binding affinities towards PBP2, tyrosine phosphatase, and FtsZ proteins. Additionally, molecular dynamics (MD) simulations underscored the notable stability of these derivatives when engaged with the FtsZ protein, as evidenced by root mean square deviation (RMSD), root mean square fluctuation (RMSF), radius of gyration (Rg), and solvent-accessible surface area (SASA). Importantly, this observation aligns with expectations, considering that griseofulvin primarily targets microtubules in eukaryotic cells, and FtsZ functions as the prokaryotic counterpart to microtubules. These findings collectively suggest the promising potential of griseofulvin and its designed derivatives as effective antibacterial agents, particularly concerning their interaction with the FtsZ protein. This research contributes to the ongoing exploration of novel antibiotics and may serve as a foundation for future drug development efforts....
Protein tyrosine kinase 6 (PTK6), also known as breast tumor kinase (BRK), serves as a non-receptor intracellular tyrosine kinase within the Src kinases family. Structurally resembling other Src kinases, PTK6 possesses an Src homology 3 (SH3) domain, an Src homology 2 (SH2) domain, and a tyrosine kinase domain (SH1). While considerable efforts have been dedicated to designing PTK6 inhibitors targeting the SH1 domain, which is responsible for kinase activity in various pathways, it has been observed that solely inhibiting the SH1 domain does not effectively suppress PTK6 activity. Subsequent investigations have revealed the involvement of SH2 and SH3 domains in intramolecular and substrate binding interactions, which are crucial for PTK6 function. Consequently, the identification of PTK6 inhibitors targeting not only the SH1 domain but also the SH2 and SH3 domains becomes imperative. Through an in silico structural-based virtual screening approach, incorporating drug repurposing and a consensus docking approach, we have successfully identified four potential ligands capable of concurrently inhibiting the tyrosine kinase domain and SH2/SH3 domains of PT6K simultaneously. This finding suggests potential pathways for therapeutic interventions in PTK6 inhibition....
Methylmalonic aciduria and homocystinuria type C protein (MMACHC) is required by the body to metabolize cobalamin (Cbl). Due to its complex structure and cofactor forms, Cbl passes through an extensive series of absorptive and processing steps before being delivered to mitochondrial methyl malonyl-CoA mutase and cytosolic methionine synthase. Depending on the cofactor attached, MMACHC performs either flavin-dependent reductive decyanation or glutathione (GSH)-dependent dealkylation. The alkyl groups of Cbl have to be removed in the presence of GSH to produce intermediates that can later be converted into active cofactor forms. Pathogenic mutations in the GSH binding site, such as R161Q, R161G, R206P, R206W, and R206Q, have been reported to cause Cbl diseases. The impact of these variations on MMACHC’s structure and how it affects GSH and Cbl binding at the molecular level is poorly understood. To better understand the molecular basis of this interaction, mutant structures involving the MMACHC-MeCbl-GSH complex were generated using in silico site-directed point mutations and explored using molecular dynamics (MD) simulations. The results revealed that mutations in the key arginine residues disrupt GSH binding by breaking the interactions and reducing the free energy of binding of GSH. Specifically, variations at position 206 appeared to produce weaker GSH binding. The lowered binding affinity for GSH in the variant structures could impact metabolic pathways involving Cbl and its trafficking....
Malvidin, one of the six most prominent anthocyanins found in various fruits and vegetables, may possess a wide range of health-promoting properties. The biological activity of malvidin and its glycosides is not entirely clear and has been relatively less frequently studied compared to other anthocyanins. Therefore, this study aimed to determine the relationship between the structural derivatives of malvidin and their anti-cholinergic and anti-inflammatory activity. The study selected malvidin (Mv) and its two sugar derivatives: malvidin 3-O-glucoside (Mv 3-glc) and malvidin 3,5-O-diglucoside (Mv 3,5-diglc). The anti-inflammatory activity was assessed by inhibiting the enzymes, specifically COX-1 and COX-2. Additionally, the inhibitory effects on cholinesterase activity, particularly acetylcholinesterase (AChE) and butyrylcholinesterase (BChE), were evaluated. Molecular modeling was also employed to examine and visualize the interactions between enzymes and anthocyanins. The results revealed that the highest inhibitory capacity at concentration 100 μM was demonstrated by Mv 3-glc in relation to AChE (26.3 ± 3.1%) and BChE (22.1 ± 3.0%), highlighting the crucial role of the glycoside substituent at the C3 position of the C ring in determining the inhibitory efficiency of these enzymes. In addition, the glycosylation of malvidin significantly reduced the anti-inflammatory activity of these derivatives compared to the aglycone form. The IC50 parameter demonstrates the following relationship for the COX-1 enzyme: Mv (12.45 ± 0.70 μM) < Mv 3-glc (74.78 ± 0.06 μM) < Mv 3,5-diglc (90.36 ± 1.92 μM). Similarly, for the COX-2 enzyme, we have: Mv (2.76 ± 0.16 μM) < Mv 3-glc (39.92 ± 3.02 μM) < Mv 3.5-diglc (66.45 ± 1.93 μM). All tested forms of malvidin exhibited higher activity towards COX-2 compared to COX-1, indicating their selectivity as inhibitors of COX-2. Theoretical calculations were capable of qualitatively replicating most of the noted patterns in the experimental data, explaining the impact of deprotonation and glycosylation on inhibitory activity. It can be suggested that anthocyanins, such as malvidins, could be valuable in the development of treatments for inflammatory conditions and Alzheimer’s disease and deserve further study....
Skin dryness and xerosis are the most common clinical manifestations of different dermatological diseases. At the same time, it was established that the expression of aquaporin 3 (AQP3) is related to the pathogenesis of atopic dermatitis, psoriasis, eczema, and vitiligo. Thus, our study was focused on the search for new molecules and the investigation of their biological activity to accelerate the expression of AQP3 in the skin’s epidermis. Aloin from an Aloe barbadensis leaf extract and trimethylglycine were chosen as new potential candidates using DiffDock computational modelling. These natural molecules demonstrated a good affinity towards the active site of AQP3 with an estimated docking score of −6.2 kcal/mol to −7.7 kcal/mol. Phyto4Health modelling predicted the anti-psoriatic, anti-inflammatory, and immunosuppressant activities that are useful in the treatment of atopic skin diseases. Furthermore, it was shown that the combination of the Aloe barbadensis leaf extract and trimethylglycine in a mass ratio of 1:1 revealed a clear synergetic effect to increase the AQP3 amount up to two times. Thus, the combination of the Aloe barbadensis extract standardized for aloin and trimethylglycine has a promising potential in drug development and the treatment of dryness....
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