Title:Identification of Novel Structurally Diverse Anaplastic Lymphoma Kinase Inhibitors Based on Pharmacophore Modeling, Virtual Screening and Molecular Docking
VOLUME: 19 ISSUE: 9
Author(s):Rong You, Lu Zhou, Liangliang Zhong, Xiaoli Li, Suwen Zhou and Yahui Tian
Affiliation:College of Chemical Engineering, Sichuan University, Sichuan, Chengdu, 610065, China.
Keywords:Anaplastic lymphoma kinase, discovery studio, pharmacophore, virtual screening, molecular docking.
Abstract:Aim and Objective: Anaplastic lymphoma kinase, an insulin receptor
protein-tyrosine kinase, is a very attractive receptor protein target for anticancer
therapy. This study was undertaken to identify novel structurally diverse anaplastic
lymphoma kinase inhibitors.
Material and Method: Pharmacophore hypotheses modeling, virtual screening and
molecular docking were used to detect potential inhibitors of anaplastic lymphoma
kinase in this paper.
Results: After the generation of ten pharmacophore hypotheses, Hypo1 with the
highest correlation value (0.981), lowest RMS (0.565), highest cost difference
(83.850) along with four typical chemical features was regarded as the best
hypothesis. Hypo1 contains a hydrogen bond acceptor, a hydrogen bong donor, a hydrophobic and a
ring aromatic feature. And then, hypo1 was validated and used to screen three databases after screened
by Lipinski’s rule of five. 3015 hits screened by Hypo1 were submitted to molecular docking based on
the crystal structure of anaplastic lymphoma kinase.
Conclusion: all the seven molecules formed hydrogen bond interaction with Met1199 as well as
formed several other hydrogen bond interactions with different residues. All of them formed Van Der
Waals interaction with hydrophobic pocket which made up of residues of Ala1148, Leu1256, Leu1196,
Leu1198 Val1130 and Val1180. Some of them also formed van der Waals interaction in somewhere
else of protein pocket.
