Novel virtual lead identification in the discovery of hematopoietic cell kinase (HCK) inhibitors: application of 3D QSAR and molecular dynamics simulation

Abstract

High level of hematopoietic cell kinase (Hck) is associated with drug resistance in chronic myeloid leukemia. Additionally, Hck activity has also been connected with the pathogenesis of HIV-1 and chronic obstructive pulmonary disease. In this study, three-dimensional (3D) QSAR pharmacophore models were generated for Hck based on experimentally known inhibitors. A best pharmacophore model, Hypo1, was developed with high correlation coefficient (0.975), Low RMS deviation (0.60) and large cost difference (49.31), containing three ring aromatic and one hydrophobic aliphatic feature. It was further validated by the test set (r = 0.96) and Fisher’s randomization method (95%). Hypo 1 was used as a 3D query for screening the chemical databases, and the hits were further screened by applying Lipinski’s rule of five and ADMET properties. Selected hit compounds were subjected to molecular docking to identify binding conformations in the active site. Finally, the appropriate binding modes of final hit compounds were revealed by molecular dynamics (MD) simulations and free energy calculation studies. Hence, we propose the final three hit compounds as virtual candidates for Hck inhibitors.

Keywords:

• Hck
• 3D QSAR
• virtual screening
• molecular docking
• molecular dynamics simulation
• free energy calculations

Disclosure statement

The authors declare no conflict of interest.

Funding

Dr. Rohit S. Bavi was financially supported by a postdoctoral fellowship from BK21 PLUS program of Ministry of Education and Human Resources Development, South Korea. This research was supported by Next-Generation BioGreen 21 Program from Rural Development Administration, Republic of Korea [Grant no. PJ01106202], and also supported by Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education [2014R1A1A2059773].