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

Area of Science:

• Oncology
• Medicinal Chemistry
• Computational Biology

Background:

• Cancer remains a leading cause of death globally, with receptor tyrosine kinases (RTKs) like c-Met and ALK playing significant roles in its progression.
• Aberrant signaling by c-Met and ALK makes them attractive therapeutic targets for cancer treatment.

Purpose of the Study:

• To construct and apply common feature pharmacophore models for ligand-based virtual screening of dual c-Met and ALK inhibitors.
• To investigate the binding interactions and stability of potential drug candidates through docking and molecular dynamics simulations.

Main Methods:

• Development of multiple common feature pharmacophore models based on known dual c-Met and ALK inhibitors.
• Ligand-based virtual screening to identify potential inhibitor compounds.
• Molecular docking studies to assess binding affinity and interaction patterns.
• Molecular dynamics simulations to evaluate the stability of key interactions for a selected compound.

Main Results:

• Pharmacophore models achieved score values ranging from 22.489 to 28.169.
• Virtual screening identified common hit compounds with high predicted affinity for both c-Met and ALK.
• Molecular dynamics revealed stable hydrogen bond interactions for compound ZINC000223394281 with Asp1222 and a 63% stable interaction with Met1199.

Conclusions:

• The developed pharmacophore models are effective for identifying dual c-Met and ALK inhibitors.
• Compound ZINC000223394281 demonstrates favorable binding characteristics and stability, suggesting its potential as a lead compound for novel cancer therapeutics targeting c-Met and ALK.