Pharmacophore feature-based virtual screening for finding potent GSK-3 inhibitors using molecular docking and dynamics simulations

Chauhan, Navneet; Anuradha, G; Basha, Syed Hussain

doi:10.6026/97320630012391

Cited by 3 publications

(3 citation statements)

References 15 publications

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“…Tideglusib’s structure was also used in a computational study to identify new GSK-3β inhibitors [ 84 ]. A pharmacophore-based virtual screening of a library of compounds was pursued using Tideglusib moieties as reference.…”

Section: Gsk-3β Inhibitionmentioning

confidence: 99%

GSK-3β Allosteric Inhibition: A Dead End or a New Pharmacological Frontier?

Balboni

Masi

Rocchia

et al. 2023

IJMS

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Most kinase inhibitors are designed to bind to highly homologous ATP-binding sites, which leads to promiscuity and possible off-target effects. Allostery is an alternative approach to pursuing selectivity. However, allostery is difficult to exploit due to the wide variety of underlying mechanisms and the potential involvement of long-range conformational effects that are difficult to pinpoint. GSK-3β is involved in several pathologies. This critical target has an ATP-binding site that is highly homologous with the orthosteric sites of other kinases. Unsurprisingly, there is also great similarity between the ATP-binding sites of GSK-3β and its isomer, which is not redundant and thus would benefit from selective inhibition. Allostery would also allow for a moderate and tunable inhibition, which is ideal for GSK-3β, because this target is involved in multiple pathways, some of which must be preserved. However, despite considerable research efforts, only one allosteric GSK-3β inhibitor has reached the clinic. Moreover, unlike other kinases, there are no X-ray structures of GSK-3β in complex with allosteric inhibitors in the PDB data bank. This review aims to summarize the state of the art in allosteric GSK-3β inhibitor investigations, highlighting the aspects that make this target challenging for an allosteric approach.

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Section: Gsk-3β Inhibitionmentioning

confidence: 99%

GSK-3β Allosteric Inhibition: A Dead End or a New Pharmacological Frontier?

Balboni

Masi

Rocchia

et al. 2023

IJMS

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“…A reversible inhibitor targeting lysine residues has been disclosed very recently [ 201 ]. Regarding GSK-3, there are some examples of irreversible covalent inhibitors targeting cysteine residues [ 202 , 203 , 204 ]. Among these drugs, compound 4 - 3 seems particularly interesting, as it targets the unique Cys14 residue found in GSK-3β and inhibits cell growth in an acute promyelocytic leukemia murine model [ 204 ].…”

Section: New Strategies For Targeting Gsk-3 In Cancer Cellsmentioning

confidence: 99%

Pathobiology and Therapeutic Relevance of GSK-3 in Chronic Hematological Malignancies

Martelli

Paganelli

Evangelisti

et al. 2022

Cells

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Glycogen synthase kinase-3 (GSK-3) is an evolutionarily conserved, ubiquitously expressed, multifunctional serine/threonine protein kinase involved in the regulation of a variety of physiological processes. GSK-3 comprises two isoforms (α and β) which were originally discovered in 1980 as enzymes involved in glucose metabolism via inhibitory phosphorylation of glycogen synthase. Differently from other proteins kinases, GSK-3 isoforms are constitutively active in resting cells, and their modulation mainly involves inhibition through upstream regulatory networks. In the early 1990s, GSK-3 isoforms were implicated as key players in cancer cell pathobiology. Active GSK-3 facilitates the destruction of multiple oncogenic proteins which include β-catenin and Master regulator of cell cycle entry and proliferative metabolism (c-Myc). Therefore, GSK-3 was initially considered to be a tumor suppressor. Consistently, GSK-3 is often inactivated in cancer cells through dysregulated upstream signaling pathways. However, over the past 10–15 years, a growing number of studies highlighted that in some cancer settings GSK-3 isoforms inhibit tumor suppressing pathways and therefore act as tumor promoters. In this article, we will discuss the multiple and often enigmatic roles played by GSK-3 isoforms in some chronic hematological malignancies (chronic myelogenous leukemia, chronic lymphocytic leukemia, multiple myeloma, and B-cell non-Hodgkin’s lymphomas) which are among the most common blood cancer cell types. We will also summarize possible novel strategies targeting GSK-3 for innovative therapies of these disorders.

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“…Structurally, GSK-3 is a two-domain kinase fold comprising a β-strand domain and an α-helix domain. The residues forming the ATP-binding site (pocket 1) are seated deep between the interface of the α-helix and β-strand domains surrounded by a hinge region and a glycine-rich loop, which is often referred to as "P-loop" [22][23][24][25] . The substrate binding site (pocket 2) is surrounded by the C-loop and the activation loop.…”

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confidence: 99%