Identification of curcumin derivatives as human LMTK3 inhibitors for breast cancer: a docking, dynamics, and MM/PBSA approach

Abstract

Human lemur tyrosine kinase-3 (LMTK3) is primarily involved in regulation of estrogen receptor-α (ERα) by phosphorylation activity. LMTK3 acts as key biomarker for ERα positive breast cancer and identified as novel drug target for breast cancer. Due to the absence of experimental reports, the computational approach has been followed to screen LMTK3 inhibitors from natural product curcumin derivatives based on rational inhibitor design. The initial virtual screening and re-docking resulted in identification of top three leads with favorable binding energy and strong interactions in critical residues of ATP-binding cavity. ADME prediction confirmed the pharmacological activity of the leads with various properties. The stability and binding affinity of leads were well refined in dynamic system from 25 ns MD simulations. The behavior of protein motion towards closure of ATP-binding cavity was evaluated based on eigenvectors by PCA. In addition, MM/PBSA calculations also confirmed the relative binding free energy of LMTK3-lead complexes in favor of the effective binding. From our study, novel LMTK3 inhibitors tetrahydrocurcumin, curcumin 4,4'-diacetate, and demethoxycurcumin have been proposed with inhibition mechanism. Further experimental evaluation on reported lead candidates might prove its role in breast cancer therapeutics.

Keywords: Free energy calculation; LMTK3; Molecular dynamics simulation; Principal component analysis; Virtual screening.

Fig. 1

2D Chemical structure of screened curcumin derivatives obtained from PubChem database

Fig. 2

Hydrogen bond interactions and hydrophobic interactions of top three lead complexes were visualized in LigPlot⁺. a CID 124072 complex, b CID 6441419 complex, c CID 5469424 complex. Color representation: hydrophobic interactions in red color arc and hydrogen bonds showed in green color dots

Fig. 3

Group properties of LMTK3–lead complexes from MD trajectories a RMSD of protein backbone atoms, b RMSD of ligand atoms. Color representation: LMTK3–CID 124072 complex in black, LMTK3–CID 6441419 complex in red, and LMTK3–CID 5469424 complex in blue

Fig. 4

a Radius of gyration (Rg) plot, b Solvent accessible surface area (SASA) plot. Color representation LMTK3 in black, LMTK3–CID 124072 complex in red, LMTK3–CID 6441419 complex in green, and LMTK3–CID 5469424 complex in blue

Fig. 5

Inter-hydrogen bond interactions. a LMTK3–CID 124072 complex, b LMTK3–CID 6441419 complex, and c LMTK3–CID 5469424 complex

Fig. 6

PCA plot constructed by eigenvector 1 vs eigenvector 2. a LMTK3, b LMTK3–CID 124072 complex, c LMTK3–CID 6441419 complex, d LMTK3–CID 5469424 complex, and e combination of LMTK3 and its lead complexes. Color representation LMTK3 in black, LMTK3–CID 124072 complex in red, LMTK3–CID 6441419 complex in green, and LMTK3–CID 5469424 complex in blue