The pharmacophoric space of glycogen synthase kinase-3beta (GSK-3beta) was explored using two diverse sets of inhibitors. Subsequently, genetic algorithm and multiple linear regression analysis were employed to select optimal combination of pharmacophores and physicochemical descriptors that access self-consistent and predictive quantitative structure-activity relationship (QSAR) against 132 training compounds ( r (2) 123 = 0.663, F = 24.6, r (2) LOO = 0.592, r (2) PRESS against 29 external test inhibitors = 0.695). Two orthogonal pharmacophores emerged in the QSAR, suggesting the existence of at least two distinct binding modes accessible to ligands within GSK-3beta binding pocket. The validity of the QSAR equation and the associated pharmacophores was established by the identification of three nanomolar GSK-3beta inhibitors retrieved from our in-house-built structural database of established drugs, namely, hydroxychloroquine, cimetidine, and gemifloxacin. Docking studies supported the binding modes suggested by the pharmacophore/QSAR analysis. In addition to being excellent leads for subsequent optimization, the anti-GSK-3beta activities of these drugs should have significant clinical implications.

Hormone sensitive lipase (HSL) has been recently implicated in diabetes and obesity, prompting attempts to discover new HSL inhibitors. Toward this end, we explored the pharmacophoric space of HSL inhibitors using four diverse sets of compounds. Subsequently, genetic algorithm and multiple linear regression analysis were employed to select optimal combination of pharmacophoric models and 2D physicochemical descriptors capable of yielding a self-consistent and predictive quantitative structure-activity relationship (QSAR) (r = 0.822, n = 99, F = 11.1, r LOO (2) = 0.521, r PRESS (2) against 23 external test inhibitors = 0.522). Interestingly, two pharmacophoric models emerged in the QSAR equation suggesting at least two binding modes. These pharmacophores were employed to screen the National Cancer Institute (NCI) list of compounds and our in-house built database of established drugs and agrochemicals. Active hits included the safe herbicidal agent bifenox (IC 50 = 0.43 microM) and the nonsteroidal anti-inflammatory naproxen (IC 50 = 1.20 microM). Our active hits undermined the traditional believe that HSL inhibitors should possess covalent bond-forming groups.

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Plant polyphenols have received considerable attention in recent years due to their ability to undergo oxidation-triggered self-polymerization, forming biocompatible versatile coatings and templated nanoparticles (NPs) that can be leveraged for a variety of biomedical applications. Here we show for the first time that untemplated NPs can be conveniently synthesized from the abundant plant polyphenol quercetin (QCT) simply by incubation with an oxidizing agent in a universal organic solvent, followed by self-assembly upon gradual addition of water. The process yielded NPs of around 180–200 nm in size with a range of colors that resembled light to medium-brown skin tones. The NPs were characterized by UV-Vis, FT-IR, and 1H-NMR spectroscopy and by dynamic light scattering and transmission electron microscopy to understand their physicochemical properties. Antioxidant and cell viability assays were also conducted to demonstrate the NPs’ free-radical scavenging activity and biocompatibility, altogether providing valuable insights into the structure and function of this emerging class of nanomaterials to guide future biomedical applications.

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Plant polyphenols have attracted attention in recent years due to their ability to undergo oxidative coupling reactions enabled by the presence of multiple phenolic hydroxyl groups, forming chemically versatile coatings and biocompatible nanoparticles (NPs) for various applications. The aim of this study was to investigate whether coffee bean aqueous extracts, which are known to be rich in polyphenols, could serve as a natural source of NP building blocks. Extracts were prepared by heating ground Arabica beans of varying roasting degrees in water with or without the addition of sodium metaperiodate or copper sulfate as an oxidizing agent, followed by filtration. NP formation was verified by dynamic light scattering and transmission electron microscopy, which revealed the presence of nano-sized particles with varying sizes and polydispersities as a function of the coffee type and oxidizing agent used. NP colors ranged from light to medium to dark brown, and particle sizes were between 44 and 250 nm with relatively low polydispersity indices. In vitro antioxidant assays showed that oxidizing agent-treated coffee NPs had lower antioxidant potency compared to air-oxidized NPs, but the free-radical scavenging activity was still retained. Coffee NPs exhibited no antimicrobial activity against common bacterial and fungal strains. Cell viability assays demonstrated that the NPs were biocompatible in human dermal fibroblasts, while exhibiting antiproliferative activity against MCF7 breast cancer cells, particularly copper sulfate-oxidized NPs. This study presents a facile and economical method to produce template-free antioxidant NPs that may be explored for various applications such as drug delivery and cosmetics.

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