Targeting the C-SH2 domain of the Syk kinase by virtual drug screening to identify potential anticancer candidates


Şansaçar M., Akçok İ., Güner H., Gencer Akçok E. B.

9 TH INTERNATIONAL BAU DRUG DESIGN CONGRESS, İstanbul, Turkey, 29 November - 02 December 2023, pp.109

  • Publication Type: Conference Paper / Summary Text
  • City: İstanbul
  • Country: Turkey
  • Page Numbers: pp.109
  • Abdullah Gül University Affiliated: Yes

Abstract

Spleen Tyrosine Kinase (SYK) which is a non-receptor kinase crosstalk pivotal signaling pathways such as PI3K, NFκB and JAK/STAT that play a role in pathogenesis of various cancers. Syk is composed of two SH2 domains at the amino terminus, followed by a catalytically active kinase domain. In this study, we aim to target the C-SH2 domain of Syk to prevent cancer progression. We employed a virtual screening of a mid-scale chemical library provided by COCONUT with 407,270 unique natural products. The chemical files of the library were converted into 3D structure files using RDKIT as preparation step for molecular docking via Smina. The target protein was selected as the crystal structure of the protein complex (PDB entry: 18A1). The existing heteroatoms and the conjugated peptide molecule were cleared, then the target binding region located on C-SH2 domain was determined using Fpocket utility to prepare the protein molecule for docking. The docking experiments yielded 25 ligand poses with a docking score less than -7.5. Three lead candidates were selected and further tested with Molecular Dynamics simulations via Gromacs for a duration of 100 ns. Post analysis of trajectories of three complexes revealed one of the hit molecules is a more promising lead candidate, which is called Preussomerin B. The multidrug resistance and poor prognosis reveal the requirement of more effective treatments for cancer. Here, we suggested a novel strategy to target Syk by in silico studies.