Computer-Aided Drug Design towards New Psychotropic and Neurological Drugs

Dorahy, Georgia; Chen, Jake Zheng; Balle, Thomas

doi:10.3390/molecules28031324

Cited by 18 publications

(11 citation statements)

References 147 publications

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“…In either case, our data highlight the possibility that appropriate chemical modification of the FX backbone may result in new compounds capable of addressing more of the residues at the ATP binding site of PI3K. Thus, our current findings may inspire and guide intelligent drug design studies, 89,90 resulting in new FX‐derivatives with improved potency/efficacy towards PI3K.…”

Section: Discussionmentioning

confidence: 73%

Fluoxetine exerts anti‐inflammatory effects on human epidermal keratinocytes and suppresses their endothelin release

Tóth,

Ádám,

Arany

et al. 2023

Experimental Dermatology

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Fluoxetine is a safe antidepressant with remarkable anti‐inflammatory actions; therefore, we aimed to investigate its effects on immortalized (HaCaT) as well as primary human epidermal keratinocytes in a polyinosinic‐polycytidylic acid (p(I:C))‐induced inflammatory model. We found that a non‐cytotoxic concentration (MTT‐assay, CyQUANT‐assay) of fluoxetine significantly suppressed p(I:C)‐induced expression and release of several pro‐inflammatory cytokines (Q‐PCR, cytokine array, ELISA), and it decreased the release of the itch mediator endothelins (ELISA). These effects were not mediated by the inhibition of the NF‐κB or p38 MAPK pathways (western blot), or by the suppression of the p(I:C)‐induced elevation of mitochondrial ROS production (MitoSOX Red labeling). Instead, unbiased activity profiling revealed that they were most likely mediated via the inhibition of the phosphoinositide 3‐kinase (PI3K) pathway. Importantly, the PI3K‐inhibitor GDC0941 fully mimicked the effects of fluoxetine (Q‐PCR, ELISA). Although fluoxetine was able to occupy the binding site of GDC0941 (in silico molecular docking), and exerted direct inhibitory effect on PI3K (cell‐free PI3K activity assay), it exhibited much lower potency and efficacy as compared to GDC0941. Finally, RNA‐Seq analysis revealed that fluoxetine deeply influenced the transcriptional alterations induced by p(I:C)‐treatment, and exerted an overall anti‐inflammatory activity. Collectively, our findings demonstrate that fluoxetine exerts potent anti‐inflammatory effects, and suppresses the release of the endogenous itch mediator endothelins in human keratinocytes, most likely via interfering with the PI3K pathway. Thus, clinical studies are encouraged to explore whether the currently reported beneficial effects translate in vivo following its topical administration in inflammatory and pruritic dermatoses.

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Section: Discussionmentioning

confidence: 73%

Fluoxetine exerts anti‐inflammatory effects on human epidermal keratinocytes and suppresses their endothelin release

Tóth,

Ádám,

Arany

et al. 2023

Experimental Dermatology

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“…Deep learning in structure-activity relationships (SAR) involves the application of multilayer neural networks to understand and predict how the structure of chemical compounds affects their biological activity. 92,[102][103][104][105] This approach is particularly revolutionary in the field of drug discovery, where identifying compounds with desired biological effects is both critical and challenging.…”

Section: Deep Learning In Structure-activity Relationships (Sar)mentioning

confidence: 99%

Top 20 Influential AI-Based Technologies in Chemistry

Ananikov

2024

Preprint

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The beginning and ripening of digital chemistry is analyzed focusing on the role of artificial intelligence (AI) in an expected leap in chemical sciences to bring this area to the next evolutionary level. The analytic description selects and highlights the top 20 AI-based technologies and 7 broader themes that are reshaping the field. It underscores the integration of digital tools such as machine learning, big data, digital twins, the Internet of Things (IoT), robotic platforms, smart control of chemical processes, virtual reality and blockchain, among many others, in enhancing research methods, educational approaches, and industrial practices in chemistry. The significance of this study lies in its focused overview of how these digital innovations foster a more efficient, sustainable, and innovative future in chemical sciences. This article not only illustrates the transformative impact of these technologies but also draws new pathways in chemistry, offering a broad appeal to researchers, educators, and industry professionals to embrace these advancements for addressing contemporary challenges in the field.

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“…Computer-aided drug design approaches, such as ligand-based and structure-based methods, represent widely exploited tools to accelerate the discovery of novel bioactive compounds [ 14 , 15 , 16 ].…”

Section: Introductionmentioning

confidence: 99%

Novel Thiazole-Based SIRT2 Inhibitors Discovered via Molecular Modelling Studies and Enzymatic Assays

Abbotto,

Casini,

Piacente

et al. 2023

Pharmaceuticals

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Recently, the development of sirtuin small molecule inhibitors (SIRTIs) has been gaining attention for the treatment of different cancer types, but also to contrast neurodegenerative disease, diabetes, and autoimmune syndromes. In the search for SIRT2 modulators, the availability of several X-crystallographic data regarding SIRT2−ligand complexes has allowed for setting up a structure-based study, which is herein presented. A set of 116 SIRT2 inhibitors featuring different chemical structures has been collected from the literature and used for molecular docking studies involving 4RMG and 5MAT PDB codes. The information found highlights key contacts with the SIRT2 binding pocket such as Van der Waals and π–π stacking with Tyr104, Phe119, Phe234, and Phe235 in order to achieve high inhibitory ability values. Following the preliminary virtual screening studies, a small in-house library of compounds (1a–7a), previously investigated as putative HSP70 inhibitors, was described to guide the search for dual-acting HSP70/SIRT2 inhibitors. Biological and enzymatic assays validated the whole procedure. Compounds 2a and 7a were found to be the most promising derivatives herein proposed.

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Computer-Aided Drug Design towards New Psychotropic and Neurological Drugs

Cited by 18 publications

References 147 publications

Fluoxetine exerts anti‐inflammatory effects on human epidermal keratinocytes and suppresses their endothelin release

Fluoxetine exerts anti‐inflammatory effects on human epidermal keratinocytes and suppresses their endothelin release

Top 20 Influential AI-Based Technologies in Chemistry

Novel Thiazole-Based SIRT2 Inhibitors Discovered via Molecular Modelling Studies and Enzymatic Assays

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