Wordom update 2: A user-friendly program for the analysis of molecular structures and conformational ensembles

Felline, Angelo; Conti, Simone; Seeber, Michele; Cecchini, Marco; Fanelli, Francesca

doi:10.1016/j.csbj.2023.01.026

Cited by 2 publications

(1 citation statement)

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“…gmx_MMPBSA program was employed to calculate the binding free energy between FAD and LSD1 using the Molecular Mechanics/Poisson–Boltzmann Surface Area (MM/PBSA) methodology. Wordom was used to perform the root-mean-squared fluctuation (RMSF) analysis. D3Pocketes was used to analyze the stability, continuity, and correlation properties of all pockets in the LSD1.…”

Section: Methodsmentioning

confidence: 99%

Mining the Dynamical Properties of Substrate and FAD Binding Pockets of LSD1: Hints for New Inhibitor Design Direction

Yang,

Liu

2024

J. Chem. Inf. Model.

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Lysine-specific demethylase 1 (LSD1), a highly sophisticated epigenetic regulator, orchestrates a range of critical cellular processes, holding promising therapeutic potential for treating diverse diseases. However, the clinical research progress targeting LSD1 is very slow. After 20 years of research, only one small-molecule drug, BEA-17, targeting the degradation of LSD1 and CoREST has been approved by the U.S. Food and Drug Administration. The primary reason for this may be the lack of abundant structural data regarding its intricate functions. To gain a deeper understanding of its conformational dynamics and guide the drug design process, we conducted molecular dynamics simulations to explore the conformational states of LSD1 in the apo state and under the influence of cofactors of flavin adenine dinucleotide (FAD) and CoREST. Our results showed that, across all states, the substrate binding pocket exhibited high flexibility, whereas the FAD binding pocket remained more stable. These distinct dynamical properties are essential for LSD1's ability to bind various substrates while maintaining efficient demethylation activity. Both pockets can be enlarged by merging with adjacent pockets, although only the substrate binding pocket can shrink into smaller pockets. These new pocket shapes can inform inhibitor design, particularly for selectively FAD-competitive inhibitors of LSD1, given the presence of numerous FAD-dependent enzymes in the human body. More interestingly, in the absence of FAD binding, the united substrate and FAD binding pocket are partitioned by the conserved residue of Tyr761, offering valuable insights for the design of inhibitors that disrupt the crucial steric role of Tyr761 and the redox role of FAD. Additionally, we identified pockets that positively or negatively correlate with the substrate and FAD binding pockets, which can be exploited for the design of allosteric or concurrent inhibitors. Our results reveal the intricate dynamical properties of LSD1 as well as multiple novel conformational states, which deepen our understanding of its sophisticated functions and aid in the rational design of new inhibitors.

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Section: Methodsmentioning

confidence: 99%