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Computational analyses of interactions between ALK-5 and bioactive ligands: insights for the design of potential

Michell O Almeida1, Clauber H S Costa2, Guelber C Gomes2

  • 1a Center of Natural Sciences and Humanities , Federal University of ABC , Santo Andre , SP , Brazil.

Journal of Biomolecular Structure & Dynamics
|November 15, 2017
PubMed

Insights

This study investigated key interactions between Activin Receptor-Like Kinase 5 (ALK-5) and cancer drug candidates using computational methods. Findings support the development of novel ALK-5 inhibitors for cancer treatment.

Area of Science:

  • Biochemistry
  • Computational Chemistry
  • Drug Discovery

Background:

  • Activin Receptor-Like Kinase 5 (ALK-5) is implicated in various cancers, including breast, lung, and pancreatic cancers.
  • A lack of crystal structures for ALK-5 inhibitor-protein complexes necessitates computational approaches for drug design.

Purpose of the Study:

  • To explore critical interactions between ALK-5 and six bioactive ligands with varying biological activities.
  • To provide molecular insights that can aid in the development of new anti-cancer drugs targeting ALK-5.

Main Methods:

  • Utilized molecular docking, molecular dynamics simulations, and free energy calculations (MM-GBSA, MM-PBSA, SIE).
  • Correlated computational binding free energy predictions with experimental data.

Main Results:

  • Calculated binding free energies showed excellent agreement with experimental data (r² = 0.88 for MM-GBSA, 0.80 for MM-PBSA, 0.94 for SIE).
  • Identified hydrogen bonds with specific residues (Lys232, Glu245, Tyr249, His283, Asp351) and a water molecule as crucial for ALK-5 inhibition.

Conclusions:

  • The study successfully elucidated key interactions between ALK-5 and six inhibitors.
  • These findings offer valuable starting points for designing novel ALK-5 targeting molecules for cancer therapy.
Keywords:
ALK-5MM-GBSAMM-PBSA and SIEcancermolecular dynamics

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