Re-Profiling and Re-purposing of FDA-Approved AntiViral Agents Against Neurological Targets of Memory and Cognition: Molecular Docking and Simulation Approach.

BACKGROUND: Dementia is a prevalent symptom of Alzheimer's Disease (AD), associated with either low levels of acetylcholine or destruction by enzymes. Such enzymes are acetylcholinesterase (AChE) and butyryl-cholinesterase (BuChE). The current research worked on re-purposing of 69 Food and Drug Administration Authority (FDA) approved antiviral agents against targets of AD, including AChE (PDB ID: 4BDT) and BuChE (PDB ID: 5LKT). METHODS: Targets proteins like AChE (PDB ID: 4BDT) and BuChE (PDB ID: 5LKT), and their PDB IDs were retrieved from the Protein Data Bank (PDB), purified through Discovery Studio Visualizer 2016 (DSV-2016), and saved in PDB format. Data of 69 FDA-approved antiviral agents and standard donepezil were obtained from different published literature, and structures were downloaded from the PubChem structure search tool. DSV-2016 was used for the purification of the targets. PyRx was utilized for the docking of 69 test agents and the standard drug donepezil. DSV-2016 was used for post-docking analysis. In addition, Physio-chemical properties, pharmacokinetics, drug-likeness, and medicinal chemistry analysis of three potential compounds (based on binding affinity) and molecular dynamic simulation (MDS) were performed using SWISSADME and AMBER24 software, respectively. RESULTS: Docking revealed the binding affinities of Saquinavir (-9.1 kcal.mol-1 ), paritaprevir (-10.8 kcal.mol-1 ), and simeprevir (-10.1 kcal.mol-1 ) with AChE. The recorded binding affinities against BuChE were Saquinavir (-11.7 kcal.mol-1 ), paritaprevir -11.2 kcal.mol-1 ), and simeprevir (-11.4 kcal.mol-1 ). Saquinavir and paritaprevir constructed one hydrogen bond with Threonine (THR38) and Glycine (GLN291), respectively. Simeprevir with Asparagine (ASN283), Valine (VAL282), and Tyrosine (TYR72), granting three hydrogen bonds. The data on lipophilicity was determined in terms of Log Po/w (ILOGP). Water solubility of Saquinavir, Paritaprevir, and Simeprevir demonstrated that the Log S (ESOL) value is much higher, and hence the mentioned three compounds are water insoluble. Saquinavir, paritaprevir, and simeprevir were subjected to molecular dynamics simulations, which showed good interactions of the test agents with BuChE compared to AChE. DISCUSSION: The study revealed that already approved 69 FDA anti-viral agents showed potential interaction with the selected targets (AChE and BuChE). Three compounds, saquinavir, paritaprevir, and simeprevir, were found with high binding affinities. As they are utilized in human life for various viral infections with known pharmacology and pharmacokinetics data, we can repurpose such a drug to be active against memory loss or cognitive problems. CONCLUSION: Based on the applied computational techniques on 69 FDA-approved agents, including molecular docking, SWISS-ADME, and MDS, we identified saquinavir, simeprevir, and paritaprevir as potential molecules modulating the action of AChE and BuChE to restore memory and cognition. Hence, it is supposed that these agents may serve as anti-Alzheimer agents. Further investigations are needed to find their therapeutic potential in in vitro and in vivo animal models.