Estimation of the ligand-binding free energy of checkpoint kinase 1 via non-equilibrium MD simulations

• Published in: Journal of molecular graphics & modelling 2020-11, Vol.100, p.107648-107648, Article 107648
• Main Authors: Mai, Nguyen Thi, Lan, Ngo Thi, Vu, Thien Y, Duong, Phuong Thi Mai, Tung, Nguyen Thanh, Phung, Huong Thi Thu
• Format: Article
• Language: English
• Subjects: CHK1; Fast pulling of ligand; Non-equilibrium molecular dynamics; Non-equilibrium work; Relative binding affinity
• ISSN: 1093-3263; 1873-4243
• DOI: 10.1016/j.jmgm.2020.107648

Checkpoint kinase 1 (CHK1) is a serine/threonine-protein kinase that is involved in cell cycle regulation in eukaryotes. Inhibition of CHK1 is thus considered as a promising approach in cancer therapy. In this study, the fast pulling of ligand (FPL) process was applied to predict the relative binding affinities of CHK1 inhibitors using non-equilibrium molecular dynamics (MD) simulations. The work of external harmonic forces to pull the ligand out of the binding cavity strongly correlated with the experimental binding affinity of CHK1 inhibitors with the correlation coefficient of R = −0.88 and an overall root mean square error (RMSE) of 0.99 kcal/mol. The data indicate that the FPL method is highly accurate in predicting the relative binding free energies of CHK1 inhibitors with an affordable CPU time. A new set of molecules were designed based on the molecular modeling of interactions between the known inhibitor and CHK1 as inhibitory candidates. Molecular docking and FPL results exhibited that the binding affinities of developed ligands were similar to the known inhibitor in interaction with the catalytic site of CHK1, producing very potential CHK1 inhibitors of that the inhibitory activities should be further evaluated in vitro. [Display omitted] •Van der Waals interaction takes a critical role in the binding of inhibitors and CHK1.•The rupture force accurately categorize the higher binding-affinity ligands.•The pulling work precisely predict the relative binding affinities of CHK1 inhibitors.•FPL is highly efficient to rank the relative binding affinity of CHK1 inhibitors.•Newly designed ligands are very promising CHK1 inhibitors.