Abstract
Fragment-Based Drug Discovery (FBDD) has become, in recent years, a consolidated approach in the drug discovery process, leading to several drug candidates under investigation in clinical trials and some approved drugs. Among these successful applications of the FBDD approach, kinases represent a class of targets where this strategy has demonstrated its real potential with the approved kinase inhibitor Vemurafenib. In the Kinase family, protein kinase CK1 isoform δ (CK1δ) has become a promising target in the treatment of different neurodegenerative diseases such as Alzheimer’s disease, Parkinson’s disease, and amyotrophic lateral sclerosis. In the present work, we set up and applied a computational workflow for the identification of putative fragment binders in large virtual databases. To validate the method, the selected compounds were tested in vitro to assess the CK1δ inhibition.
Highlights
Protein kinase CK1 isoform δ (CK1δ) belongs to the family of CK1 Kinases (Casein Kinase 1), which in turn belongs to the class of Ser-Thr Kinases; seven isoforms of this family were identified in mammals: α, β, γ1, γ2, γ3, δ, ε
A library of around 272,000 commercially available fragment compounds was screened in silico using an integrated structure-based approach based on different techniques such as molecular docking, molecular dynamics (MD), and pharmacophore filter
The choice to generate such a great number of poses for each ligand was taken in order not to rely on the scoring function ability to prioritize the best binding mode for each compound, since fragments can have multiple binding modes that are similar from an energetic and qualitative point of view and are difficult to distinguish for scoring functions that are trained upon mature, lead-like, compounds
Summary
Protein kinase CK1δ belongs to the family of CK1 Kinases (Casein Kinase 1), which in turn belongs to the class of Ser-Thr Kinases; seven isoforms of this family were identified in mammals: α, β, γ1, γ2, γ3, δ, ε. CK1δ and the other isoforms of the family of CK1 can phosphorylate Ser or Thr residues in sequences such as (P)Ser/Thr-X1-2 -Ser/Thr, where (P)Ser/Thr indicates a Ser or Thr pre-phosphorylated residue [2]; CK1, needs the substrate to bealready phosphorylated. It has been demonstrated that a set of amino acids with acidic character in the direction of the N-terminal withrespect to Ser/Thr target residue or an acidic residue in position 3 (preferably Asp) can provide for the lack of the prephosphorylated amino acid [3,4]. About 140 substrates (in vitro or in vivo) recognized by CK1 have been described [1]
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