Dual potent c-Met and ALK inhibitors: from common feature pharmacophore modeling to structure based virtual screening

Abstract

Everyday plenty of people succumb to various forms of cancer across the world and it stands as one of the main reasons of death in our today’s life. Receptor tyrosine kinases (RTKs) are a class of receptors involved in cancer progression. Since aberrant signaling has critical roles in cancer, both c-Met and ALK enzymes are regarded as attractive oncology targets for therapeutic objects. A number of potent dual inhibitors of c-Met and ALK are reported in literature that in the present work we based them to construct multiple common feature pharmacophore models and then applied them for ligand-based virtual screening. The score values of the models ranged from 22.489 to 28.169. The retrieved compounds from virtual screening were subjected to the docking study and the interaction pattern of common hits between two enzymes with high predicted affinity has been investigated. To this end, common hit compound ZINC000223394281 (z1) was directed to the molecular dynamics study and the results indicated that the hydrogen bond interaction between this compound and Asp1222 was mostly stable during the equilibrium time range. The life time of hydrogen bond made between the complex of ALK and Met1199 was also stable in 63%.

Keywords:

• Cancer
• c-Met
• ALK
• multi-target inhibitors
• docking

Disclosure statement

No potential conflict of interest was reported by the author(s).

Additional information

Funding

This work was supported by the Vice-Chancellor for Research, Shiraz University of Medical Sciences under Grant number 1396-01-12-16535.