Drug repurposing of FDA-approved Bisantrene and Canagliflozin as potential CHK1 inhibitors: insights from molecular docking and molecular dynamics simulations

Checkpoint kinase 1 (CHK1) is an essential serine/threonine kinase involved in DNA damage response and cell cycle control. Dysregulated CHK1 activation has been found to be associated with tumor progression and resistance to various therapies in many cancer types and thus is an attractive target for development of anti-cancer drugs. In the present study, we use a structural-based virtual screening approach and screened 3500 FDA-approved drugs retrieved from Drug Bank. The molecular docking studies, which illustrated several potential candidates, showed that both Bisantrene and Canagliflozin achieved higher binding energies (-9.2 and -9.5 kcal/mol, respectively) than the reference inhibitor Prexasertib (-7.5 kcal/mol) according to docking with InstaDock. Interaction profiling showed that these ligands mainly occupied the ATP-binding site, interacting with the crucial catalytic residues (LEU15, GLY16, GLU17, GLY18, TYR20, GLU22, VAL23 and LYS38) through hydrogen bonds, pi-sigma interactions and hydrophobic contacts which implied stable and specific binding modes. Similarly, molecular dynamics simulations for 500 ns with GROMACS indicate studying docked complexes stability by reporting RMSD and overall compactness. PCA and FEL analyses further corroborated that both CHK1-Bisantrene and CHK1-Canagliflozin complexes had similar stability when compared to the CHK1-Prexasertib complex reference. Energy calculations and solvent exposure supported by these favorable binding and structural parameters. These results bring up Bisantrene and Canagliflozin as potential CHK1-binding candidates for repurposing in the form of anticancer drugs and recommended for further validation by in-vitro and in-vivo.