A steered molecular dynamics mediated hit discovery for histone deacetylases

Area of Science:

• Computational chemistry
• Drug discovery
• Molecular modeling

Background:

• Histone deacetylase inhibitors (HDACIs) are promising cancer therapeutics.
• Virtual high-throughput screening (vHTS) is crucial for identifying novel HDACIs.
• Accurately modeling ligand-protein flexibility in vHTS remains a challenge.

Purpose of the Study:

• To develop an integrated approach combining vHTS and steered molecular dynamics (SMD).
• To efficiently identify potential HDACIs and characterize their binding potencies.
• To address the challenge of ligand-protein flexibility in vHTS.

Main Methods:

• Implemented a hybrid pharmacophore-based and structure-based vHTS method.
• Utilized steered molecular dynamics (SMD) to investigate molecular interactions.
• Analyzed SMD-driven force profiles to assess binding potencies.

Main Results:

• The hybrid vHTS identified hits with favorable physico-chemical features against class I HDACs.
• Pharmacophore-based screening improved the quality of vHTS outcomes.
• SMD analysis effectively filtered hits, identifying those with higher binding potencies.

Conclusions:

• vHTS and SMD are complementary tools for accelerating hit identification.
• The integrated approach provides an efficient method for drug design.
• This strategy enhances the characterization of binding potencies in a flexible environment.