Non-Hodgkin’s lymphomas are a diverse collection of lymphoproliferative cancers that are much less predictable than Hodgkin’s lymphomas with a far greater tendency to metastasize to extranodal sites. A quarter of non-Hodgkin’s lymphoma cases develop at extranodal sites and the majority of them involve nodal and extranodal sites. The most common subtypes include follicular lymphoma, chronic/small lymphocytic leukaemia, mantel cell lymphoma, and marginal zone lymphoma. Umbralisib is one of the latest PI3Kδ inhibitors in clinical trials for several hematologic cancer indications. In this study, new umbralisib analogues were designed and docked to the active site of PI3Kδ, the main target of the phosphoinositol-3-kinase/Akt/mammalian target of the rapamycin pathway (PI3K/AKT/mTOR). This study resulted in eleven candidates, with strong binding to PI3Kδ with a docking score between −7.66 and −8.42 Kcal/mol. The docking analysis of ligand–receptor interactions between umbralisib analogues bound to PI3K showed that their interactions were mainly controlled by hydrophobic interactions and, to a lesser extent, by hydrogen bonding. In addition, the MM-GBSA binding free energy was calculated. Analogue 306 showed the highest free energy of binding with −52.22 Kcal/mol. To identify the structural changes and the complexes’ stability of proposed ligands, molecular dynamic simulation was used. Based on this research finding, the best-designed analogue, analogue 306, formed a stable ligand–protein complex. In addition, pharmacokinetics and toxicity analysis using the QikProp tool demonstrated that analogue 306 had good absorption, distribution, metabolism, and excretion properties. Additionally, it has a promising predicted profile in immune toxicity, carcinogenicity, and cytotoxicity. In addition, analogue 306 had stable interactions with gold nanoparticles that have been studied using density functional theory calculations. The best interaction with gold was observed at the oxygen atom number 5 with −29.42 Kcal/mol. Further in vitro and in vivo investigations are recommended to be carried out to verify the anticancer activity of this analogue.

The use of aromatase inhibitors is an established therapy for estrogen-dependent breast cancer in postmenopausal women. However, the only commercially available aromatase inhibitor, letrozole, is not highly selective; in addition to aromatase, it has an affinity for binding to desmolase, an enzyme involved in steroidogenesis, which explains the main side effects. Therefore, we designed new compounds based on the structure of letrozole. More than five thousand compounds were constructed based on the letrozole structure. Then, these compounds were screened for their binding ability toward the target protein, aromatase. Quantum docking, Glide docking, and ADME studies showed 14 new molecules with docking scores of ≤−7 kcal/mol, compared to the docking score of −4.109 kcal/mol of the reference, letrozole. Moreover, molecular dynamics (MD) and post-MD MM-GBSA calculations were calculated for the top three compounds, and the results supported in their interaction’s stability. Finally, the density-functional theory (DFT) study applied to the top compound to study the interaction with gold nanoparticles revealed the most stable position for the interaction with the gold nanoparticles. The results of this study confirmed that these newly designed compounds could be useful starting points for lead optimization. Further in vitro and in vivo studies are recommended for these compounds to verify these promising results experimentally.

The enhancement of drug solubility and bioavailability is a significant challenge in pharmaceutical sciences. Solid dispersions have emerged as a promising strategy to address this issue. This research provides a comprehensive review of the advancements in solid dispersion technologies, focusing on the classification and characteristics of different generations of solid dispersions. The study highlights the evolution from first-generation solid dispersions, utilizing crystalline carriers, to fourth-generation systems that incorporate water-insoluble polymers and surfactants to improve drug release and bioavailability. The efficacy of various carriers and techniques, such as hot melt extrusion and solvent evaporation, are critically analyzed. Additionally, the impact of these advancements on poorly soluble anticancer drugs and herbal medicines is discussed, providing insights into future research directions and potential therapeutic applications.