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Pharmacophore-Aided Virtual Screening and Molecular Dynamics Simulation Identifies TrkB Agonists for Treatment of

Ibitayo Abigail Ademuwagun1,2, Gbolahan Oladipupo Oduselu1,3, Solomon Oladapo Rotimi1,2

  • 1Covenant University Bioinformatics Research (CUBRe), Covenant University, Ota, Nigeria.

Bioinformatics and Biology Insights
|March 10, 2023
PubMed

Insights

Researchers identified novel, potent tropomyosin receptor kinase B (TrkB) agonists for treating cyclin-dependent kinase-like 5 (CDKL5) deficiency disorders (CDDs). These compounds show promise as alternative or combinatorial therapies for CDD management.

Area of Science:

  • Neuroscience
  • Pharmacology
  • Computational Chemistry

Background:

  • Cyclin-dependent kinase-like 5 (CDKL5) deficiency disorders (CDDs) present significant therapeutic challenges.
  • Deficient tropomyosin receptor kinase B (TrkB) signaling is implicated in CDD pathogenesis.
  • 7,8-dihydroxyflavone (7,8-DHF), a TrkB agonist, has shown therapeutic potential in CDD models.

Purpose of the Study:

  • To identify novel TrkB agonists with higher potency than 7,8-DHF for CDD treatment.
  • To discover potential alternative or combinatorial drug candidates for CDD management.

Main Methods:

  • Pharmacophore modeling and virtual screening of compound databases.
  • In silico pharmacokinetic and ADMET profiling.
  • Molecular docking and molecular dynamics simulations.

Main Results:

  • Identified 691 compounds matching the 7,8-DHF pharmacophore.
  • Discovered at least 6 compounds with superior binding affinity to TrkB compared to 7,8-DHF.
  • Selected compounds exhibited favorable in silico pharmacokinetic and ADMET properties.
  • Molecular simulations confirmed unique ligand interactions for top candidates.

Conclusions:

  • Novel TrkB agonists with enhanced potency and drug-like properties were identified computationally.
  • These compounds represent promising candidates for experimental validation in CDD models.
  • Further research is warranted to assess the therapeutic efficacy of these novel agonists in CDD management.
Keywords:
CDKL5 deficiency disordersmolecular dynamics simulationpharmacophoreseizurevirtual screening

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