LSD1-Based Reversible Inhibitors Virtual Screening and Binding Mechanism Computational Study.

Area of Science:

• Biochemistry
• Epigenetics
• Medicinal Chemistry

Background:

• Histone lysine-specific demethylase 1 (LSD1) is a critical epigenetic regulator implicated in various cancers.
• Existing irreversible LSD1 inhibitors face challenges including toxicity and limitations due to the enzyme's binding pocket characteristics.
• There is a need for novel, reversible LSD1 inhibitors with improved safety and efficacy profiles.

Purpose of the Study:

• To identify and characterize novel reversible inhibitors of LSD1.
• To explore new chemical scaffolds for LSD1-targeted cancer therapies.
• To provide a theoretical basis for the rational design of LSD1 inhibitors.

Main Methods:

• Employed structure-based and ligand-based virtual screening strategies.
• Utilized molecular docking, pharmacophore modeling, and drug-likeness evaluations.
• Performed ADMET screening, molecular dynamics simulations, and binding free energy calculations.

Main Results:

• Screened over 2 million compounds, identifying five hit compounds categorized as amide or 1,2,4-triazolo-4,3-α-quinazoline derivatives.
• Compound 4 (Comp4) demonstrated the highest binding affinity among the identified inhibitors.
• Analysis revealed van der Waals interactions as the primary binding force, with FAD contributing to binding stability and reduced off-target effects.

Conclusions:

• The study successfully identified novel reversible LSD1 inhibitors with potential therapeutic applications.
• The findings expand the chemical diversity of known LSD1 inhibitors and offer new insights for synthetic chemists.
• This work lays a theoretical foundation for developing safer and more effective LSD1-targeted cancer treatments.