Ganoderic Acid A targeting leucine‐rich repeat kinase 2 involved in Parkinson's disease–A computational study

Abstract Objective This study aims to find the most promising Ganoderma lucidium targeting LRRK2 involved in PD. Methods First ADMET analysis was performed for five compounds followed by molecular docking of each compound. Then, we perform molecular dynamics simulation of all five compounds and finally MMGBSA of all five compounds. Results Based on molecular dynamics and MMGBSA result we reach the conclusion that Ganoderic Acid A (GAA) is the most promising compound targeting LRRK2. Therefore, GAA needs further validation through in vitro and in vivo studies. Conclusion Ganoderma lucidum exhibits cytotoxic, hepatoprotective, antioxidative, anticancer, and antinociceptive activities. This study predicted that Ganoderma lucidum could even be used to treat neurological disorders like PD. This study suggest that the best‐identified molecule against LRRK2 is GAA and it needs rigorous in vitro and in vivo validations.


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AHMAD neuroprotective; small-molecule LRRK2 inhibitors and antisense oligonucleotides have been developed and are now considered suitable for clinical exposure. 8 In this computational study, we have considered Ganoderma lucidum, also known as "Reishi mushroom," under the category of medicinal mushroom. Ganoderma lucidum has immune-stimulating activities, antiinflammatory and antiallergenic properties for cancer, and can be used for treating and managing neurological disorders like PD and AD. In this study, we took the five most promising molecules in the Reishi mushroom extract: Ganoderic Acid A, Ganoderic Acid D, Ganoderic Acid F, Ganoderenic Acid B, and Ganoderenic Acid D. [9][10][11] In our study, we performed molecular docking for the five compounds mentioned above, and finally, we performed molecular dynamics simulation for all the five compounds. Ultimately, this study aims to find the most promising compound from Ganoderma lucidum extract, which can be used for in vitro and in vivo studies.

| ADMET analysis
To calculate the pharmacokinetic and pharmacological properties of these five compounds, SWISSADME was used.

| Molecular docking
Docking Studies were performed with AutoDock 4.2.6, using the standard procedures. The 3D coordinates of the LRRK2 protein were retrieved from the RCSB database with the PDB ID 7LHT and five ligands from the PubChem database. A grid box with x, y, and z directions was generated, keeping the grid spacing at 0.375 Å, and flexible multiple ligand docking was performed using a Perl script. The outputs were analyzed and visualized in Discovery Studio Visualizer. where ∆Gobind = binding free energy, Gcomplex = free energy of the complex, G-protein = free energy of the target protein, and Gligand = free energy of the ligand.

| ADMET analysis
The ADMET analysis of the selected molecules was done. ADME abbreviation stands for Absorption, Distribution, Drug Metabolism, and Excretion. It describes the absorption, distribution, drug metabolism, and excretion of a substance or medication. Solubility and permeability are critical characteristics that influence the oral absorption rate. As soon as the medication is dissolved, it circulates throughout the body and is divided into compartments. Drug distribution into tissues and organs is governed by pharmacokinetic characteristics such as plasma protein binding, lipophilicity, and phospholipids, three essential variables to consider. Drug metabolism is the process by which a drug molecule is broken down or altered enzymatically, followed by excretion. The most important metric for determining pharmaceutical excretion in humans is renal clearance, which is essential for assessing pharmaceutical excretion in humans. Lipinski's five rule also referred to as the Pfizer rule of five, requires that oral pharmaceuticals have a molecular weight of less than 500, fewer than five hydrogen bond donors and acceptors, and a distribution ratio of less than five to be evaluated for approval. All the five compounds follow Lipinski's rule of five.
The result of the ADMET analysis of five compounds is mentioned in Table 1.

| Molecular docking
The blind molecular docking of the selected five molecules from the

| Molecular dynamics simulation
The assessment of the complex stability between the LRRK2 and the screened molecules from the Ganoderma lucidum extract was done by subjecting them to molecular dynamics simulation in order

| DISCUSS ION
Molecular docking is the most extensively utilized technique since it allows tiny compounds to interact with targets at the atomic level.
Using this technique, we can better understand small molecule behavior in specific protein targets and predict the structure of ligandreceptor complexes, which is critical for drug development. In this study, we took the five most potent molecules of Ganoderma lucidum extract, which include Ganoderic Acid A (GAA), Ganoderic Acid Wistar rats against rotenone induced Parkinsonian affect. 18 A single case study of self-medication of Ganoderma lucidium in which a 50-year-old male showed positive effects by improving motor skills, thought process, as well as emotion regulation, strengthens the clinical research findings. 19 Thus, GAA can be used for in vitro and vivo studies, which can lead to drug development of PD.

| CON CLUS ION
Ganoderma lucidum exhibits cytotoxic, hepatoprotective, antioxidative, anticancer, and antinociceptive activities. This study predicted that Ganoderma lucidum could even be used to treat neurological disorders like PD. This study suggest that the best-identified molecule against LRRK2 is GAA and it needs rigorous in vitro in vivo validations.

AUTH O R CO NTR I B UTI O N S
Complete paper which includes idea generation, methodolgy, results, writing, editing and reviewing.

ACK N OWLED G M ENTS
I would like to thank my supervisor to provide me the opportunity to do this study as my Master of Science Dissertation project.

FU N D I N G I N FO R M ATI O N
Not received.

CO N FLI C T O F I NTE R E S T
The author proclaims no competing interests.