Related Experiment Video
Updated: Feb 17, 2026
Detection of Nuclear Blebbing and DNA Leakage in Mammalian Cells by Immunofluorescence
Published on: January 17, 2025
Computational Exploration for Lead Compounds That Can Reverse the Nuclear Morphology in Progeria
Shailima Rampogu1, Ayoung Baek1, Minky Son1
1Division of Applied Life Science (BK21 Plus), Plant Molecular Biology and Biotechnology Research Center (PMBBRC), Systems and Synthetic Agrobiotech Center (SSAC), Research Institute of Natural Science (RINS), Gyeongsang National University (GNU), 501 Jinju-daero, Jinju 52828, Republic of Korea.
Abstract:
Progeria is a rare genetic disorder characterized by premature aging that eventually leads to death and is noticed globally. Despite alarming conditions, this disease lacks effective medications; however, the farnesyltransferase inhibitors (FTIs) are a hope in the dark. Therefore, the objective of the present article is to identify new compounds from the databases employing pharmacophore based virtual screening. Utilizing nine training set compounds along with lonafarnib, a common feature pharmacophore was constructed consisting of four features. The validated Hypo1 was subsequently allowed to screen Maybridge, Chembridge, and Asinex databases to retrieve the novel lead candidates, which were then subjected to Lipinski's rule of 5 and ADMET for drug-like assessment. The obtained 3,372 compounds were forwarded to docking simulations and were manually examined for the key interactions with the crucial residues. Two compounds that have demonstrated a higher dock score than the reference compounds and showed interactions with the crucial residues were subjected to MD simulations and binding free energy calculations to assess the stability of docked conformation and to investigate the binding interactions in detail. Furthermore, this study suggests that the Hits may be more effective against progeria and further the DFT studies were executed to understand their orbital energies.
Insights
Researchers identified potential new drugs for Hutchinson-Gilford progeria syndrome (HGPS) using virtual screening. Farnesyltransferase inhibitors (FTIs) show promise for treating this rare premature aging disorder.
Area of Science:
- Medicinal Chemistry
- Computational Drug Discovery
- Genetics
Background:
- Hutchinson-Gilford progeria syndrome (HGPS) is a rare genetic disorder causing premature aging and death.
- Effective treatments for HGPS are lacking, highlighting the need for novel therapeutic strategies.
Purpose of the Study:
- To identify novel drug candidates for HGPS using pharmacophore-based virtual screening.
- To explore the potential of farnesyltransferase inhibitors (FTIs) as therapeutic agents for HGPS.
Main Methods:
- Construction of a four-feature pharmacophore model based on known FTIs.
- Virtual screening of Maybridge, Chembridge, and Asinex databases against the pharmacophore model.
- In silico drug-likeness assessment using Lipinski's rule of 5 and ADMET properties.
- Molecular docking, molecular dynamics (MD) simulations, and binding free energy calculations.
- Density Functional Theory (DFT) studies for orbital energy analysis.
Main Results:
- Identified novel lead candidates with potential therapeutic value for HGPS.
- Two compounds exhibited superior docking scores and crucial residue interactions compared to reference drugs.
- MD simulations and binding free energy calculations confirmed the stability and detailed binding interactions of the identified compounds.
- DFT studies provided insights into the electronic properties of the potential drug candidates.
Conclusions:
- The identified compounds show promise as effective treatments for HGPS.
- Further experimental validation is warranted to confirm the efficacy and safety of these novel FTIs for HGPS treatment.
