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3D-QSAR-aided design of potent c-Met inhibitors using molecular dynamics simulation and binding free energy

Pavithra K Balasubramanian1, Anand Balupuri1, Swapnil P Bhujbal1

  • 1a Department of Biomedical Sciences, College of Medicine , Chosun University , Gwangju 501-759 , Republic of Korea.

Journal of Biomolecular Structure & Dynamics
|July 26, 2018
PubMed

Insights

This study identifies key residues for inhibiting mesenchymal-epithelial transition factor (c-Met) kinase and designs novel imidazo[4,5-b]pyrazine derivatives as potent c-Met inhibitors for cancer therapy.

Area of Science:

  • Medicinal Chemistry
  • Computational Biology
  • Drug Discovery

Background:

  • Mesenchymal-epithelial transition factor (c-Met) is a receptor tyrosine kinase implicated in cancer progression.
  • Over-expression of c-Met is observed in various cancers, making it a significant therapeutic target.

Purpose of the Study:

  • To identify crucial residues involved in c-Met kinase inhibition.
  • To design novel imidazo[4,5-b]pyrazine derivatives as potent c-Met inhibitors.

Main Methods:

  • Molecular docking to identify key active site residues.
  • Molecular dynamics simulations and free energy calculations for validation.
  • Comparative Molecular Field Analysis (CoMFA) and Comparative Molecular Similarity Indices Analysis (COMSIA) for quantitative structure-activity relationship (QSAR) modeling.

Main Results:

  • Key residues Tyr1230, Met1211, Asp1222, Tyr1159, Met1160, Val1092, Ala1108, and Leu1157 were identified as crucial for binding stability.
  • Predictive CoMFA and COMSIA models (q² > 0.74) were generated.
  • Twenty-seven novel c-Met inhibitors were designed, showing enhanced potency compared to existing compounds.

Conclusions:

  • The study successfully identified critical residues for c-Met inhibition.
  • Developed predictive QSAR models to guide drug design.
  • Designed novel, potent c-Met inhibitors with potential for cancer therapy.
Keywords:
CoMFACoMSIAMMGBSAc-Met kinasedesignentropy calculationsfree energy calculationmolecular dynamics simulation

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