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10 pages, 977 KiB

Open AccessArticle

Identifying p56^lck SH2 Domain Inhibitors Using Molecular Docking and In Silico Scaffold Hopping

by Priyanka Samanta and Robert J. Doerksen

Appl. Sci. 2024, 14(10), 4277; https://doi.org/10.3390/app14104277 - 17 May 2024

Bacterial infections are the second-leading cause of death, globally. The prevalence of antibacterial resistance has kept the demand strong for the development of new and potent drug candidates. It has been demonstrated that Src protein tyrosine kinases (TKs) play an important role in [...] Read more.

Bacterial infections are the second-leading cause of death, globally. The prevalence of antibacterial resistance has kept the demand strong for the development of new and potent drug candidates. It has been demonstrated that Src protein tyrosine kinases (TKs) play an important role in the regulation of inflammatory responses to tissue injury, which can trigger the onset of several severe diseases. We carried out a search for novel Src protein TK inhibitors, commencing from reported highly potent anti-bacterial compounds obtained using the Mannich reaction, using a combination of e-pharmacophore modeling, virtual screening, ensemble docking, and core hopping. The top-scoring compounds from ligand-based virtual screening were modified using protein structure-based design approaches, and their binding to the Src homology-2 domain of p56^lck TK was predicted using ensemble molecular docking. We have prepared a database of 202 small molecules and have identified six novel top hits that can be subjected to further investigation. We have also performed in silico ADMET property prediction for the hit compounds. This combined computer-aided drug design approach can serve as a starting point for identifying novel TK inhibitors that could be further subjected to in vitro studies and validation of antimicrobial activity. Full article

(This article belongs to the Special Issue Research on Organic and Medicinal Chemistry)

14 pages, 4345 KiB

Open AccessArticle

Thermal Analysis in the Evaluation of Solid Lipid Microparticles in the Form of Aqueous Dispersion and Fine Powder

by Eliza Wolska and Géza Regdon, Jr.

Appl. Sci. 2023, 13(24), 13282; https://doi.org/10.3390/app132413282 - 15 Dec 2023

Cited by 1 | Viewed by 613

Abstract

In the presented study, an attempt was made to investigate the most important attributes of solid lipid microparticles (SLM) using thermal analysis (DSC/TG) in order to determine the importance of this technique in the research and development of lipid microparticles. Particularly interesting in [...] Read more.

In the presented study, an attempt was made to investigate the most important attributes of solid lipid microparticles (SLM) using thermal analysis (DSC/TG) in order to determine the importance of this technique in the research and development of lipid microparticles. Particularly interesting in our studies were drug–lipid interactions and modifications of the SLM matrix structure induced by the production method (the hot emulsification method) and further processing (e.g., spray drying), as well as changes occurring during the stability studies. Cyclosporine A, indomethacin and spironolactone were used as model active substances incorporated into SLM. The conducted research demonstrated the significant potential of DSC/TG, especially for the analysis of SLM in the form of fine powder. The method of sample preparation, consisting of evaporation of water at room temperature, turned out to be crucial for the DSC/TG analysis of SLM dispersion. In the case of the tested SLM, the basic and usually the only observed thermal transformation in the DSC spectrum was the endothermic peak associated with the lipid forming a microsphere matrix. This peak is the main source of information about the properties and stability of the tested SLM. The obtained results show that glyceryl behenate (Compritol) is a significantly better lipid for forming lipid microparticles than stearic acid. Although thermal transformations of the incorporated drug substances are not directly visible in the DSC spectra, their impact on the SLM properties can be assessed indirectly, based on changes in the lipid melting point and the shape of the DSC and TG peaks and curves. DSC/TG studies confirmed the lack of an effect of the spray drying process on the properties of drug-loaded SLM with Compritol. Studies have also shown up to a 2-year stability of SLM with CsA. Full article

(This article belongs to the Special Issue Research on Organic and Medicinal Chemistry)

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40 pages, 11080 KiB

Open AccessReview

Terpenes as Potential Anti-Alzheimer’s Disease Agents

by Elisabete Lima and Jorge Medeiros

Appl. Sci. 2024, 14(9), 3898; https://doi.org/10.3390/app14093898 - 2 May 2024

Viewed by 390

Abstract

Alzheimer’s disease (AD), a slowly progressive neurodegenerative disorder, is the main cause of dementia worldwide. However, currently, the approved drugs to combat AD are effective only in treating its symptoms. In fact, an efficacious treatment for this complex and multifactorial disorder remains to [...] Read more.

Alzheimer’s disease (AD), a slowly progressive neurodegenerative disorder, is the main cause of dementia worldwide. However, currently, the approved drugs to combat AD are effective only in treating its symptoms. In fact, an efficacious treatment for this complex and multifactorial disorder remains to be discovered, demanding the urgent development of new therapeutic approaches for the disease, such as the use of bioactive secondary metabolites (SMs) from natural sources. Sessile organisms, like plants, are unable to escape from adverse environmental conditions and must therefore create their own defense. Their main defense strategy is chemical defense that includes the production of an enormously diverse array of bioactive SMs, such as terpenes and their derivatives. This largest and most diverse group of plant SMs also provide the treatment of several diseases due to their broad-spectrum bioactivities, for example, anticancer, antioxidant, and anti-inflammatory properties. Thus, the evaluation of the neuroprotective potential of terpenes is imperative. It is known that the major AD clinical indications (CIs) are extracellular senile plaques of amyloid-β (Aβ) protein, intracellular hyperphosphorylated tau (τ) neurofibrillary tangles (NFTs), uncommon neuroinflammatory response, oxidative stress, and synaptic and neuronal dysfunction. Therefore, terpenes that may decrease these CIs might be used for AD treatment. Surely, terpenes targeting more than one AD pathogenic mechanism, multi-target drug ligands (MTDLs), have the potential to become a leading AD treatment. Thus, this review analyzes, for each CI, the scaffolds of the selected terpenes leading to the highest activity. Full article

(This article belongs to the Special Issue Research on Organic and Medicinal Chemistry)

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