Current Issue : January-March Volume : 2025 Issue Number : 1 Articles : 5 Articles
Lipophilicity is an essential parameter of a compound that determines the solubility and pharmacokinetic properties that determine the transport of the drug to the molecular target. Dimers of dipyridothiazines are diazaphenothiazine derivatives exhibiting diverse anticancer potential in vitro, which is related to their affinity for histone deacetylase. In this study, the lipophilicity of 16 isomeric dipyridothiazine dimers was investigated theoretically and experimentally by reversed-phase thinlayer chromatography (RP-TLC) in an acetone–TRIS buffer (pH = 7.4). The relative lipophilicity parameter RM0 and specific hydrophobic surface area b were significantly intercorrelated, showing congeneric classes of dimers. The parameter RM0 was transformed into parameter logPTLC by use of the calibration curve. Molecular descriptors, ADMET parameters and probable molecular targets were determined in silico for analysis of the pharmacokinetic profile of the tested compounds showing anticancer activity. The analyzed compounds were tested in the context of Lipinski’s rule of five, Ghose’s rule and Veber’s rule, confirming their bioavailability....
Recent studies have discovered that aryl-substituted pyrido[2,1-a]isoquinolines have the potential to be highly active DPP IV inhibitors. In previous studies, we reported a novel synthetic approach for the construction of their sulfur-containing bioisosteric [1,4]thiazino[3,4-a]isoquinolines analogues, incorporating an additional aryl substituent. The present study aims to investigate the DPP IV inhibitory activity and cytotoxicity of the synthesized molecules by in vitro assay. The geometry optimization and molecular docking of the synthesized compounds were used to determine their binding modes to the active site of DPP IV. The docking analysis revealed that the energy-minimized poses of the studied compounds are close to the most important selectivity cliffs for DPP IV inhibition, forming hydrogen bonds and hydrophobic interactions with them. These results can be considered as a preliminary step towards further structural activity modifications....
Background/Objectives: Multiple sclerosis (MS) is an autoimmune disorder of the central nervous system (CNS) characterized by myelin and axonal damage with a globally rising incidence. While there is no known cure for MS, various disease-modifying treatments (DMTs) exist, including those targeting Sphingosine-1-Phosphate Receptors (S1PRs), which play important roles in immune response, CNS function, and cardiovascular regulation. This study focuses on understanding how nonsynonymous single nucleotide polymorphisms (rs1299231517, rs1323297044, rs1223284736, rs1202284551, rs1209378712, rs201200746, and rs1461490142) in the S1PR1’s active site affect the binding of endogenous ligands, as well as different drugs used in MS management. Methods: Extensive molecular dynamics simulations and linear interaction energy (LIE) calculations were employed to predict binding affinities and potentially guide future personalized medicinal therapies. The empirical parameters of the LIE method were optimized using the binding free energies calculated from experimentally determined IC50 values. These optimized parameters were then applied to calculate the binding free energies of S1P to mutated S1PR1, which correlated well with experimental values, confirming their validity for assessing the impact of SNPs on S1PR1 binding affinities. Results: The binding free energies varied from the least favorable −8.2 kcal/mol for the wild type with ozanimod to the most favorable −16.7 kcal/mol for the combination of siponimod with the receptor carrying the F2055.42L mutation. Conclusions: We successfully demonstrated the differences in the binding modes, interactions, and affinities of investigated MS drugs in connection with SNPs in the S1PR1 binding site, resulting in several viable options for personalized therapies depending on the present mutations....
Aptamers are shortDNA or RNA sequences that adopt 3D structures and can bind to protein targets with high binding affinity and specificity. Aptamers exhibit excellent tissue penetration, are inexpensive to produce, and can be internalized by cells. Therefore, aptamers are attractive targeting ligands to direct the delivery of theranostic agents to the desired cells. Epithelial cell adhesion molecule (EpCAM) is a tumor-associated antigen that is aberrantly overexpressed on many epithelialderived cancers, including on cholangiocarcinoma (CCA) cells. Its expression on treatment-resistant cancer stem cells, along with its abundance in the CCA tumor microenvironment, highlights the need to develop EpCAM-targeted therapies for CCA. Herein, an in silico approach was used to design and screen DNA aptamers capable of binding to the EpCAM monomer and homodimer. Two aptamers, PLD01 and PLD02, met the selection criteria and were validated in vitro. Both aptamers exhibited high affinity for EpCAM+ CCA cells, with negligible binding to EpCAM- leukemia cells. Modified versions of PLD01 and PLD02 were successfully incorporated into the membranes of milk-derived nanovesicles. PLD01-functionalized nanovesicles enabled EpCAM-targeted delivery of the therapeutic cargo to CCA cells. In summary, these EpCAM-targeting aptamers can be utilized to direct the delivery of theranostic agents to EpCAM-expressing cells....
Background/Objectives: Skin hyperpigmentation is a biological process that results in an excessive production of melanin and is highly regulated by several mechanisms, tyrosinase being one of the key enzymes involved. Current reported inhibitors lack clinical efficacy, show toxic side effects, have poor bioavailability, or low formulation compatibility. The aim of this study was to design a new effective tyrosinase inhibitor for topical hyperpigmentation and anti-aging treatments. Methods: Homology modeling was used to build the tridimensional structure of human tyrosinase, and virtual docking was used to predict molecule–enzyme binding modes. The tyrosinase activity of the designed and synthesized compounds was assessed and water solubility was determined by HPLC. Cell assays were performed to determine melanin content, cytotoxicity, wound healing, anti-glycation, antioxidation, and autophagy efficacy. Gene expression and miRNA levels were quantified by qPCR and chromatin accessibility by ATAC-Seq. Human reconstructed epidermis was used to test the depigmenting efficacy as well as the skin irritation potential. Results: The 3D structure of human tyrosinase was designed and validated. The new molecule could effectively inhibit human tyrosinase and melanin synthesis in 2D monocultures and a 3D epidermis model. Two melanogenesis-related miRNAs were increased in treated cells. Anti-glycation, antioxidant, mitochondria protection, autophagy activation, and wound healing properties were also observed, with special emphasis on epigenetics. Conclusions: The designed molecule is a potential candidate to be used as a depigmenting and anti-aging agent, with suitable properties to be introduced in final product formulations for dermatology or cosmetics treatments....
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