Scaffold Repurposing of in-House Chemical Library toward the Identification of New Casein Kinase 1 δ Inhibitors

Abstract

Recent studies have highlighted the key role of Casein kinase 1 δ (CK1δ) in the development of several neurodegenerative pathologies, such as Alzheimer's disease (AD), Parkinson's disease (PD), and amyotrophic lateral sclerosis (ALS). So far, CK1δ inhibitors are noncovalent ATP competitive ligands and no drugs are currently available for this molecular target, hence the interest in developing new CK1δ inhibitors. The study aims to identify new inhibitors able to bind the enzyme; by a dual approach in silico/in vitro, the virtual screening has been performed on an in-house chemical library, which was previously designed and synthesized for other targets. The work can, therefore, be seen in the scaffold repurposing logic. The proposed strategy has led to the identification of two hits, having a novel scaffold in the landscape of CK1δ inhibitors and with an activity in the micromolar range.

Structure-Based Scaffold Repurposing toward the Discovery of Novel Cholinesterase Inhibitors

“… 57 In silico scaffold repurposing is an inexpensive and emerging tool to ascertain new applications of existing drugs. 58 , 59 Moreover, structure-based virtual screening identified raltegravir, an HIV-1 integrase inhibitor, as an adjuvant in the treatment of cancer. 60 Hence, it is crucial to use an in silico scaffold repurposing approach to discover novel lead pharmaceuticals for any disease, including AD.…”

“…Similarly, different classes of drugs such as angiotensin receptor blockers and calcium channel blockers have shown promising results for the treatment of AD , Moreover, structure-based virtual screening identified raltegravir, an HIV-1 integrase inhibitor, as an adjuvant in the treatment of cancer . Hence, it is crucial to use an in silico scaffold repurposing approach to discover novel lead pharmaceuticals for any disease, including AD.…”

Novel Pyrazolo[3,4-c]pyridine Antagonists with Nanomolar affinity for A1 / A3 Adenosine Receptors: Binding Kinetics and Exploration of their Binding Profile Using Mutagenesis Experiments, MD simulations and TI/MD calculations

“…We, 19 and other groups, [12][13][14][15][16][17][18] are motivated to identify new hits from virtual screening of ARs 19,22 and modify them to lead compounds. However, the possibility of re-purposing compounds from in-house libraries 15 is an exciting opportunity and cost-effective process.…”

“…We, 19 and other groups, [12][13][14][15][16][17][18] are motivated to identify new hits from virtual screening of ARs 19,22 and modify them to lead compounds. However, the possibility of re-purposing compounds from in-house libraries 15 is an exciting opportunity and cost-effective process. We identified here the pyrazolo[3,4-c]pyridines L2-L10, A15, A17 with a phenyl or isopropyl group at 3-position, an anilino group at 7-position and a cyano-, or chloro-or aminomethyl group or N-(arylmethyl)-2aminomethyl group at 5-position with nanomolar to mid-nanomolar binding affinities measured with the BRET method.…”

“…10,11 The binding mode of agonists, like adenosine and 5'-N-ethylcarboxamidoadenosine (NECA), [2][3][4] as well as of several antagonists [5][6][7][8][9] has been revealed in crystallographic A2A structures since 2008 or the complexes with Gs protein solved using electron cryo-microscopy in 2018. 4 These experimental structures can help to understand the binding interactions of ARs with ligands and provide templates for structure-based drug design as other groups [12][13][14][15][16][17][18] and our 19 group performed. For example, in our previous work, from in silico screening of Maybridge HitFinder Library 19 using the experimental structure of A2AR with ZM241385 (PDB ID 3EML) 5 we identified new hits, with low micromolar affinities against A3R measured using radio-labeled assays.…”