Related Experiment Video
Updated: Jul 20, 2025
Quantitative Structure-Activity Relationship, Activity Prediction, and Molecular Dynamics of Non-nucleotide Reverse Transcriptase Inhibitors
Published on: May 9, 2025
LSD1-Based Reversible Inhibitors Virtual Screening and Binding Mechanism Computational Study
Zhili Yin1, Shaohui Liu1, Xiaoyue Yang1
1School of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou 450001, China.
Abstract:
As one of the crucial targets of epigenetics, histone lysine-specific demethylase 1 (LSD1) is significant in the occurrence and development of various tumors. Although several irreversible covalent LSD1 inhibitors have entered clinical trials, the large size and polarity of the FAD-binding pocket and undesired toxicity have focused interest on developing reversible LSD1 inhibitors. In this study, targeting the substrate-binding pocket of LSD1, structure-based and ligand-based virtual screenings were adopted to expand the potential novel structures with molecular docking and pharmacophore model strategies, respectively. Through drug-likeness evaluation, ADMET screening, molecular dynamics simulations, and binding free energy screening, we screened out one and four hit compounds from the databases of 2,029,554 compounds, respectively. Generally, these hit compounds can be divided into two categories, amide (Lig2 and Comp2) and 1,2,4-triazolo-4,3-α-quinazoline (Comp3, Comp4, Comp7). Among them, Comp4 exhibits the strongest binding affinity. Finally, the binding mechanisms of the hit compounds were further calculated in detail by the residue free energy decomposition. It was found that van der Waals interactions contribute most to the binding, and FAD is also helpful in stabilizing the binding and avoiding off-target effects. We believe this work not only provides a solid theoretical foundation for the design of LSD1 substrate reversible inhibitors, but also expands the diversity of parent nucleus, offering new insights for synthetic chemists.
Insights
Researchers identified novel reversible inhibitors for histone lysine-specific demethylase 1 (LSD1), a key epigenetic target in cancer. These compounds show strong binding affinity, offering new therapeutic strategies and insights for drug design.
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.
Related Concept Videos
01:16Protein-Drug Binding: Mechanism and Kinetics
Various forces drive these interactions, including hydrogen bonds, hydrophobic interactions, ionic bonds, electrostatic interactions, and van der Waals forces. These bonds enable drugs to bind to specific sites on proteins,...
02:40Ligand Binding Sites
Protein-ligand interactions are quite specific; even though numerous potential ligands surround a cellular protein at any given time, only a particular ligand can bind to that protein. Moreover, a ligand binds only to a dedicated area on the surface of the protein, known as the...
00:49Ligand Binding and Linkage
01:49Conserved Binding Sites
Binding sites are often located in large pockets, and if their location on a protein’s surface is unknown, it can be predicted using various approaches. The energetic method computationally...
02:18The Equilibrium Binding Constant and Binding Strength
02:04Protein-protein Interfaces