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A computer aided drug discovery based discovery of lead-like compounds against KDM5A for cancers using pharmacophore
Asma Tariq1, Hafiz Muzzammel Rehman1, Rana Muhammad Mateen2
1School of Biochemistry and Biotechnology, University of the Punjab, Lahore, Punjab, Pakistan.
Abstract:
KDM5A over-expression mediates cancer cell proliferation and promotes resistance toward chemotherapy through epigenetic modifications. As its complete mechanism of action is still unknown, there is no KDM5A specific drug available at clinical level. In the current study, lead compounds for KDM5A were determined through pharmacophore modeling and high-throughput virtual screening from Asinex libraries containing 0.5 million compounds. These virtual hits were further evaluated and filtered for ADMET properties. Finally, 726 compounds were used for docking analysis against KDM5A. On the basis of docking score, 10 top-ranked compounds were selected and further evaluated for non-central nervous system (CNS) and CNS drug-like properties. Among these compounds, N-{[(7-Methyl-4-oxo-1,2,3,4-tetrahydrocyclopenta [c] chromen-9-yl) oxy]acetyl}-l-phenylalanine (G-score: -11.363 kcal/mol) was estimated to exhibit non-CNS properties while 2-(3,4-Dimethoxy-phenyl)-7-methoxy-chromen-4-one (G-score: -7.977 kcal/mol) was evaluated as CNS compound. Docked complexes of both compounds were finally selected for molecular dynamic simulation to examine the stability. This study concluded that both these compounds can serve as lead compounds in the quest of finding therapeutic agents against KDM5A associated cancers.
Insights
Researchers identified potential lead compounds for KDM5A inhibitors to combat cancer. These compounds, identified via virtual screening and molecular docking, show promise for developing new KDM5A-targeted cancer therapies.
Area of Science:
- Biochemistry
- Pharmacology
- Computational Chemistry
Background:
- KDM5A overexpression drives cancer proliferation and chemotherapy resistance via epigenetic modifications.
- The precise mechanism of KDM5A remains incompletely understood, limiting the development of targeted drugs.
- No KDM5A-specific drugs are currently available for clinical use.
Purpose of the Study:
- To identify novel lead compounds for KDM5A inhibition through computational methods.
- To evaluate potential drug candidates for their efficacy and drug-like properties.
- To lay the groundwork for developing new therapeutic agents against KDM5A-associated cancers.
Main Methods:
- Utilized pharmacophore modeling and high-throughput virtual screening of a large compound library.
- Filtered virtual hits based on ADMET properties and performed docking analysis against KDM5A.
- Selected top-ranked compounds for molecular dynamic simulations to assess stability and drug-like properties (CNS/non-CNS).
Main Results:
- Identified N-{[(7-Methyl-4-oxo-1,2,3,4-tetrahydrocyclopenta [c] chromen-9-yl) oxy]acetyl}-l-phenylalanine (non-CNS) and 2-(3,4-Dimethoxy-phenyl)-7-methoxy-chromen-4-one (CNS) as promising lead compounds.
- Both compounds demonstrated favorable docking scores and stability through molecular dynamic simulations.
- The study successfully filtered and ranked compounds for their potential as KDM5A inhibitors.
Conclusions:
- The identified compounds, N-{[(7-Methyl-4-oxo-1,2,3,4-tetrahydrocyclopenta [c] chromen-9-yl) oxy]acetyl}-l-phenylalanine and 2-(3,4-Dimethoxy-phenyl)-7-methoxy-chromen-4-one, can serve as valuable lead structures.
- These lead compounds offer a promising starting point for the development of novel therapeutic agents targeting KDM5A in cancer treatment.
- Further research and development are warranted to advance these compounds towards clinical application for KDM5A-driven cancers.
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