INTRODUCTION:

Alzheimer's disease is a neurodegenerative disorder with a complex etiology. The drug targets involved in Alzheimer's disease are beta-amyloid and cholinesterase. The primary class of drugs used in this disease treatment are cholinesterase inhibitors, which increase the level of acetylcholine in the brain.

The pathogenesis of Alzheimer's disease includes neurofibrillary tangles and amyloid deposition, leading to an imbalance in the activity of kinases and phosphatases in the tryptophan degradation pathway and neuroinflammation. Neuroinflammation is the most critical symptom of Alzheimer's disease, and there is no complete drug that deals with all the above factors¹. Potential heterocyclic compounds are hit compounds for developing new drugs for neurodegenerative diseases. Drug development includes a multifactorial approach. It consists of the identification of promising heterocyclic scaffolds with known biological effects². Nitrogen-containing heterocyclics play a pivotal role in drug discovery. Approximately 60 percent of small molecule drugs have nitrogen rings in their molecular framework. Pyridine stands out as a crucial heterocyclic core in exploring biologically active agents, including those with antiepileptic, antidepressant, and antianxiety agents. The polar nature and the electron-donating lone pair on the nitrogen atom make pyridine an excellent resource for enhancing its bioavailability and pharmacokinetic properties, including its solubility. The diazine group, encompassing pyridazine, pyrimidine, and pyrazine, is characterized by a benzene ring where two carbon atoms are substituted with Nitrogen. The basicity of diazine rings is weaker than pyridine because of the inductive effect of the second Nitrogen. These diazines demonstrate various biological properties. including antibacterial, antituberculosis, anti-HIV, diuretic, anticonvulsant, and antidepressant. Medicinal chemists commonly leverage the imidazole ring's ionization capabilities to enhance lead molecules' pharmacokinetic characteristics. This feature acts as a solution to optimize the solubility and bioavailability parameters of inadequately soluble compounds. The triazole, a medically advantageous five-membered heterocyclic moiety, serves as a fundamental structural element in various CNS drug classes. Computer-aided drug design is a process that uses computer-generated models to study how drugs interact with target receptors or proteins. By creating in silico molecular models, researchers can better understand the interactions between drugs and their targets.³ SAR correlates with the physicochemical properties of biological activities. Molecular docking is used to study the possible orientations of ligand ligands towards the receptor. The best binding pose with minimum binding energy and maximum interactions is chosen⁴. Docking methods commonly used have limitations, as they cannot treat targets and ligands flexibly or dynamically. In recent years, various advancements in proteomics, genomics, and computational science have created different docking techniques incorporating protein-ligand flexibility and their various binding conformations⁵.

MATERIALS AND METHODS:

The 3D receptor structure with PDB ID 1EVE was obtained from the RCSB Database (www.rcsb.org/pdb). 1EVE refers to a 3D structure of the anti-Alzheimer drug Donepezil, bound to its target Acetylcholinesterase. This target is classified as a Serine Hydrolase under the class of enzymes, and it is complexed with a selective inhibitor, E20. The structure contains only one chain (A), with a resolution of 2.50 Å with an R-value of 0.188.PyRX software was utilized for this study. It is developed in Python and can be downloaded and executed on any computer that meets the required configuration and specifications. A Dell Intel Core i5 8th Generation system with 8 GB RAM, running Windows 10 software and featuring HD Graphics, was used for this study.⁶

The Sdf format of ligands was downloaded from Pub Chem to obtain input files. Auto dock Vina was used for docking using PyRX, which provides the Vina algorithm. The receptor and ligand were loaded and prepared for docking. The PDBQT files were then prepared, and the grid box was established by selecting the protein and ligand and proceeding by clicking forward. After the grid box was generated, it was adjusted according to the docking requirements, and the level of docking exhaustiveness was specified by entering the relevant numerical value. Finally, the docking process was initiated by clicking the forward button, and the poses, affinities, and RMSD values were obtained. The PDB/PDBQT protein and vina output files were then opened in PYMOL for analysis.

Auto dock:

The process involved running Grid and Auto Dock by setting and saving the grid parameters and executing Auto Grid Four to generate the map files. The auto dock was then run using the generated executable files, and the Histogram showing the docking results was opened in a notepad.⁷

Swiss ADME:

Drug-likeliness RADAR of compounds with good activity and ADME prediction were obtained using Swiss ADME Bioavailability. Redocking was performed using the same procedure, and the binding affinity was obtained⁸

RESULTS AND DISCUSSION:

Fig 1: Receptor 1EVE

Fig 2: Binding sites of receptor

Fig.: 3 Docked image of ligand ID 1010723 with receptor

Fig 4: Bioavailability Radar Boiled egg diagram ID 10107823

Fig 5: Bioavailability Radar Boiled egg diagram of Donepezil

Table 1: Docking results

LIGAND	Lowest Binding Energy (PyRX)*	RMSD	Lowest Binding Energy (Auto Dock)*
(3r,4s)-1-benzyl-3-nitro-4-phenyl pyrrolidine (ID 10107823)	-8.5	0	-9.12
5-bromo-1-[(2r,4s,5r)-4-hydroxy-5-(hydroxymethyl)oxolan-2-yl]pyrimidine-2,4-dione,( ID 6035)	-8.2	0
6-[4-(2-piperidine-1-ylethoxy)phenyl]-3-pyridin-4-ylpyrazolo[1,5-a]pyrimidine, (ID 11524144)	-7.7	0
6-(4-methoxyphenyl)-3-pyridin-4-ylpyrazolo[1,5-a]pyrimidine, (ID 5329457)	-7.5	0
4-(5-pyridine-4-yl-1h-1,2,4-triazole-3-yl)pyridine-2-carbonitrile, (ID 5288320)	-7.2	0	-5.84
5-pyridine-4-yl-1,2-dihydro-1,2,4-triazole-3-thione (ID 924033)	-6.8	0
DONEPEZIL	-7.6	0

N=9

Table 2: Swiss ADME Prediction

Property	DONEPEZIL	(3r,4s)-1-benzyl-3-nitro-4-phenyl pyrrolidine (ID 10107823
lipophilicity	Log p 3.92	Log p 2.41
Water solubility	Log s-4.81	Log s-3.71
Absorption	GI -high BBB-yes	GI -high BBB-No
Drug Likeliness	Lipinski-0 Violation	Lipinski-0 Violation
Synthetic accessibility	3.36	3.12

From the above results, it can be depicted that the heterocyclic Nitrogen ligands of PubChem ID 10107823, 6035 are equally or more active ligands as per docking predictions to inhibit the cholinesterase enzyme and to produce an increase in central cholinergic activity, which may cure neurodegenerative diseases Alzheimer’s and Dementia. The results of the remaining four compounds are also promising. Further synthetic modifications and QSAR studies can be performed in these compounds to generate lead compounds with anticholinesterase activity, good blood-brain barrier penetration, and low toxicity. Any new compound of medical interest is a treasure that significantly improves human conditions.

CONCLUSION:

Six nitrogen heterocyclics containing Pyrrolidine, Pyrimidine, and Triazole nuclei were randomly selected from a chemical database and were tested for anticholinesterase activity to identify active compounds for Alzheimer’s disease and other neurodegenerative disorders. Donepezil in combination with cholinesterase (PDBID 1EVE) receptor was utilized for the study. Most of the tested compounds crossed the benchmark of required docking parameters to qualify as potential drug candidates. Since this is only a prediction of activity, more in vivo testing and toxicity studies must be done to establish them as a drug candidate. Nitrogen contains heterocyclic compounds that have proven to be bioactive for various diseases.

ACKNOWLEDGEMENT:

I acknowledge Mrs. Sindhu Elizabeth Kuriakose for the help rendered.

REFERENCES:

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Received on 30.01.2024 Modified on 05.03.2024

Asian J. Pharm. Res. 2024; 14(2):121-124.

DOI: 10.52711/2231-5691.2024.00020