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Investigating the Inhibitory Effects of Paliperidone on RAGEs: Docking, DFT, MD Simulations, MMPBSA, MTT, Apoptosis,
Akash Pratap Singh1, Shaban Ahmad2, Ahona Roy3
1Department of Botany, Maitreyi College, University of Delhi, New Delhi 110021, India.
Abstract:
Chronic diseases such as diabetes and cancer are the leading causes of mortality worldwide. Receptors for Advanced Glycation End products (RAGEs) are ubiquitous factors that catalyse Advanced Glycation End products (AGEs), proteins, and lipids that become glycated from sugar ingestion. RAGEs are cell surface receptor proteins and play a broad role in mediating the effects of AGEs on cells, contributing to modifying biological macromolecules like proteins and lipids, which can cause Reactive Oxygen Species (ROS) generation, inflammation, and cancer. We targeted RAGE inhibition analysis and screening of United States Food and Drug Administration (FDA) libraries through molecular docking studies that identified the four most suitable FDA compounds: Zytiga, Paliperidone, Targretin, and Irinotecan. We compared them with the control substrate, Carboxymethyllysine, which showed good binding interaction through hydrogen bonding, hydrophobic interactions, and π-stacking at active site residues of the target protein. Following a 100 ns simulation run, the docked complex revealed that the Root Mean Square Deviation (RMSD) values of two drugs, Irinotecan (1.3 ± 0.2 nm) and Paliperidone (1.2 ± 0.3 nm), were relatively stable. Subsequently, the Molecular Mechanics Poisson-Boltzmann Surface Area (MMPBSA) determined that the Paliperidone molecule had a high negative energy of -13.49 kcal/mol, and the Absorption, Distribution, Metabolism, and Excretion (ADME) properties were in control for use in the mentioned cases. We extended this with many in vitro studies, including an immunoblotting assay, which revealed that RAGEs with High Mobility Group Box 1 (HMGB1) showed higher expression, while RAGEs with Paliperidone showed lower expressions. Furthermore, cell proliferation assay and Apoptosis assay (Annexin-V/PI staining) results revealed that Paliperidone was an effective anti-glycation and anti-apoptotic drug-however, more extensive in vivo studies are needed before its use.
Insights
This study identifies Paliperidone as a potential drug to inhibit Receptors for Advanced Glycation End products (RAGEs), which are linked to chronic diseases. In vitro studies show Paliperidone effectively reduces RAGEs and offers anti-glycation and anti-apoptotic benefits, warranting further investigation.
Area of Science:
- Biochemistry
- Molecular Biology
- Pharmacology
Background:
- Chronic diseases like diabetes and cancer are major global health burdens.
- Receptors for Advanced Glycation End products (RAGEs) mediate the harmful effects of Advanced Glycation End products (AGEs), contributing to oxidative stress, inflammation, and cancer.
- Targeting RAGEs presents a potential therapeutic strategy for managing these chronic conditions.
Purpose of the Study:
- To identify potential inhibitors of RAGEs from FDA-approved drug libraries using molecular docking.
- To evaluate the binding efficacy and stability of identified compounds with RAGEs.
- To assess the in vitro anti-glycation and anti-apoptotic effects of the most promising drug candidate.
Main Methods:
- Molecular docking studies were performed on FDA drug libraries against RAGEs.
- Stability of docked complexes was assessed using 100 ns molecular dynamics simulations.
- Binding free energy was calculated using Molecular Mechanics Poisson-Boltzmann Surface Area (MMPBSA).
- In vitro validation included immunoblotting assays, cell proliferation assays, and apoptosis assays (Annexin-V/PI staining).
Main Results:
- Molecular docking identified four FDA compounds, with Paliperidone showing significant binding interactions with RAGEs.
- Molecular dynamics simulations indicated stable docked complexes for Irinotecan and Paliperidone.
- Paliperidone exhibited favorable binding energy (-13.49 kcal/mol) and acceptable ADME properties.
- In vitro studies confirmed that Paliperidone reduces RAGE expression and demonstrates anti-glycation and anti-apoptotic activity.
Conclusions:
- Paliperidone is a promising candidate for RAGE inhibition, showing potential as an anti-glycation and anti-apoptotic agent.
- The findings support further in vivo investigation of Paliperidone for chronic disease management.
- Targeting RAGEs with FDA-approved drugs like Paliperidone offers a viable therapeutic avenue.
