In silico design, modelling and molecular mechanisms of Axl receptor tyrosine kinase inhibitors

Area of Science:

• Biochemistry
• Molecular Biology
• Oncology

Background:

• Receptor tyrosine kinases (RTKs) regulate cellular metabolism, and their upregulation drives angiogenesis in metastatic cancers.
• Axl RTK is overexpressed in metastatic cancer cells, promoting uncontrolled growth and angiogenesis.
• Kinase inhibitors offer a therapeutic strategy by arresting signal transduction pathways in malignant cells.

Purpose of the Study:

• To identify novel small molecule inhibitors targeting the Axl kinase domain.
• To analyze the binding modes and interactions of inhibitors with the Axl kinase domain.

Main Methods:

• Pharmacophore-based virtual screening of multiple small molecule databases (CHEMBL32, ChemDiv, Chemspace, Mcule, MolProt, PubChem, Zinc) using a reference macrocyclic inhibitor (7YS).
• Molecular docking, molecular dynamics simulations, MM-PBSA calculations for binding energy estimation, and principal component analysis for trajectory analysis.
• Analysis of the binding interactions of the reference inhibitor, ATP, and seven identified hit molecules at the catalytic and regulatory sites of the Axl kinase domain.

Main Results:

• Seven hit molecules were identified through virtual screening and docking studies.
• Molecular dynamics and binding energy calculations provided insights into the stability and affinity of the identified inhibitors.
• Analysis revealed distinct binding modes of inhibitors, ATP, and the reference compound at both catalytic and regulatory sites of Axl kinase.

Conclusions:

• The study successfully identified potential small molecule inhibitors for Axl kinase.
• The findings provide a molecular basis for the design of novel anti-cancer therapeutics targeting Axl-driven malignancies.
• Further investigation into these hit molecules could lead to the development of effective cancer treatments.