👤 Nolwenn Samson

BackgroundDrug repurposing offers a rapid, cost-effective approach for discovering therapies against multiple targets.ObjectiveHere, we screen virtual ligand libraries consisting of 3468 approved drugs against 11 protein targets associated with Alzheimer's disease (AD).MethodsWe employ blind molecular docking, and target amyloid-β (Aβ), microtubule-associated protein tau (MAPT), Apolipoprotein E4 (APOE4), acetylcholinesterase (AChE), butyrylcholinesterase (BChE), amyloid-β protein precursor (AβPP), β-secretase (BACE1), brain-derived neurotrophic factor (BDNF), presenilin 1 (PSEN1) and 2 (PSEN2), and α-synuclein (SNCA) proteins using AutoDock Vina.ResultsNotably, multitarget binding recurs among the top-10 ligands with Ergotamine and Dihydroergotamine potentially binding 8; Dutasteride 7; Drospirenone and Nilotinib 6; Adapalene and Conivaptan 5; Bromocriptine 4; and Rolapitant, Irinotecan, Plerixafor, Saquinavir, and Telmisartan 3, out of 11 protein targets. As such, we reveal potential binding sites for ergot alkaloids, steroids, retinoids, antivirals, angiotensin receptor blockers, and Neurokinin 1 (NK1) receptor antagonists on multiple AD targets. Importantly, the therapeutic potential of the top-scoring ligands is confounded by pharmacokinetics and adverse-effects. For example, poor blood-brain barrier (BBB) penetration, and vasoconstriction, discount ergot-alkaloid use in AD. Likewise, potential toxicity limits prolonged use of steroids, Nilotinib, Adapalene, and Irinotecan. Conversely, BBB penetration, neuronal protection, oral availability, anti-inflammation, and anti-hypertension, admit Angiotensin receptor blockers (ARB), (Telmisartan/Candesartan); Antidiuretic hormone (ADH) inhibitors (Conivaptan/Tolvaptan); and of the NK1 receptors antagonists (Rolapitant/Netupitant) use in AD.ConclusionsOur multitarget screening identifies selective synergistic AD modulators, such as ARB, ADH and NK1 receptor inhibitors, and simplifies drug discovery by focusing on the most promising candidates for experimental validation. Show less

Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by brain aggregates of amyloid-β (Aβ) plaques and Tau tangles. Despite extensive research, effective therapy for AD remains elusive. Polyoxometalates (POMs), a class of inorganic compounds with diverse chemical structures and properties, are emerging as potential candidates for AD treatment due to their ability to target key molecular players implicated in disease pathogenesis, such as Aβ, acetylcholinesterase (AChE) and butyryl acetylcholinesterase (BChE). Here, we use molecular docking to predict the binding pose and affinities of POMs to 10 top targets associated with AD. First, we validate our method by replicating experimentally known binding of POMs to Aβ (ΔG = - 9.67 kcal/mol), AChE (ΔG = - 9.39 kcal/mol) and BChE (ΔG = - 10.86 kcal/mol). Then, using this method, we show that POM can also bind β-secretase 1 (BACE1, ΔG = - 10.14 kcal/mol), presenilin 1 (PSEN1, ΔG = - 10.65 kcal/mol), presenilin 2 (PSEN2, ΔG = - 7.94 kcal/mol), Amyloid Precursor Protein (APP, ΔG = - 7.26 kcal/mol), Apolipoprotein E (APOE4, ΔG = - 10.05 kcal/mol), Microtubule-Associated Protein Tau (MAPT, ΔG = - 5.28 kcal/mol) depending on phosphorylation, and α-synuclein (SNCA, ΔG = - 7.64 kcal/mol). Through such binding, POMs offer the potential to mitigate APP cleavage, Aβ oligomer neurotoxicity, Aβ aggregation, thereby attenuating disease progression. Overall, our molecular docking study represents a powerful tool in the discovery of POM-based therapeutics for AD, facilitating the development of novel treatments for AD. Show less

Cell proliferation is a fundamental process required for organismal development, growth, and maintenance. Failure to control this process leads to several diseases, including cancer. Zinc finger protein 768 (ZNF768) is an emerging transcription factor that plays key roles in driving proliferation. In addition to controlling a gene network supporting cell division, ZNF768 physically interacts and inhibits the activity of the tumor suppressor p53. Although the importance of ZNF768 in promoting cell proliferation has been well demonstrated in vitro, the physiological and pathological roles of ZNF768 in vivo are still unknown. Here, we report the generation and characterization of a ZNF768 null mouse model. ZNF768 null mice are viable but show a growth defect early in life. Mouse embryonic fibroblasts (MEFs) isolated from ZNF768 null embryos exhibit higher p53 levels, premature senescence, and higher sensitivity to genotoxic stress. In line with these findings, ZNF768 null mice showed increased radiosensitivity. This effect was associated not only with higher expression of a subset of p53 target genes, but also with alterations in genes regulating transmembrane receptor signaling, cell adhesion, and growth. Because ZNF768 levels are elevated in tumors, we tested the impact of ZNF768 loss on cancer development in mice. Here, we show that ZNF768 deletion was sufficient to repress lung tumor development in a KRAS Show less

The RAS→RAF→MEK→ERK pathway is hyperactivated in the majority of human lung adenocarcinoma (LUAD). However, the initial activating mutations induce homeostatic feedback mechanisms that limit ERK activity. How ERK activation reaches the tumor-promoting levels that overcome the feedback and drive malignant progression is unclear. We show here that the lung lineage transcription factor NKX2-1 suppresses ERK activity. In human tissue samples and cell lines, xenografts, and genetic mouse models, NKX2-1 induces the ERK phosphatase DUSP6, which inactivates ERK. In tumor cells from late-stage LUAD with silenced NKX2-1, re-introduction of NKX2-1 induces DUSP6 and inhibits tumor growth and metastasis. We show that DUSP6 is necessary for NKX2-1-mediated inhibition of tumor progression in vivo and that DUSP6 expression is sufficient to inhibit RAS-driven LUAD. Our results indicate that NKX2-1 silencing, and thereby DUSP6 downregulation, is a mechanism by which early LUAD can unleash ERK hyperactivation for tumor progression. Show less