Background: ALK was a receptor tyrosine kinase (RTK) belonging to the insulin receptor
superfamily. Many ALK fusion partner genes have been identified in NSCLC, such as NPM, EML4,
TFG, KLC1, KIF5B and PTPN3. There had been many reports of potent ALK inhibitors discovered by
innovative pharmaceutical companies.
Methods: A series of 2,4-diarylaminopyrimidine-containing ALK inhibitors were synthesized by Kim as
the data set for the 3D-QSAR studies are described in this paper. CoMFA and CoMSIA models were
performed using Sybyl X 2.0 package. Molecular docking analysis was carried out using Surflex-Dock in
the SYBYL-X 2.0 package.
Results: Firstly, The detailed contour analysis of ligand-based CoMFA and CoMSIA models enabled us
to identify several structural requirements as mentioned in above paragraph for the observed inhibitory
activities: 1) R1
: bulk substituents, electronegative substitutes at para-site of R1
electropositive substitutes at 2-site and 5-site of R1
aromatic ring, hydrophobic, and hydrogen bond
acceptor (favorable); 2) R2
: small substitutes, hydrophobic and H-bond donor (favorable); electrostatic
field had little effect on biological activity; 3) R3
: medium sized substitutes and electronegative
substituents at orth-site of R3
aromatic group, H-bond donor at 2-site and 3-site of R3
aromatic group, and
hydrogen bond acceptor at the para-site of R3
aromatic group (favorable); small substitutes and
electrostatic field at para-site of R3
ring, and hydrophobic had little effect on biological activity.
Scondly, the conformations obtained after MD is more stable than the docked conformations. MD
simulation is performed in a more realistic environment, and much closer to physiological conditions.
Conclusion: The contour maps obtained from the CoMFA, CoMSIA analysis provided useful
information about the intermolecular interactions of the inhibitors with the surrounding environment. In
addition, the 3D-QSAR models, molecular docking and MD simulations exhibit a good consistency
indicating that the derived models are reliable and robus. The results from the 3D-QSAR models,
molecular docking, and MD simulations should lead to a better understanding of the structural features
needed to create novel potential ALK inhibitors.