Beyond the Bioavailability Barrier: Comparative In-Silico ADMET Profiling and Molecular Docking of Ayurvedic Phytoconstituents vs. Allopathic Alternatives for Neurodegenerative Disorders

Neurodegenerative disorders are chronic and progressive conditions, with irreversible damage of central nervous system neurons, which causes the loss of various functions, including cognitive, sensory, behavioral, and motor functions. Of these, Alzheimer's disease (AD) and Parkinson's disease (PD) are the most common and significant health problems worldwide. While the synuclein is associated with AD and forms amyloid-β plaques, tau protein aggregates, oxidative stress, and neuronal death leading to memory and cognitive decline, the degeneration of dopaminergic neurons in the substantia nigra occurs in PD, leading to tremors, rigidity, bradykinesia, and postural instability. Other factors that contribute considerably to the progression 

of the disease include mitochondrial dysfunction, neuroinflammation, excitotoxicity and oxidative damage. [1,2]

Neurodegenerative disorders are becoming a more common problem in the world because of the advancement of age, environment, metabolic disorders and genetic predisposition. The present allopathic medicines are used primarily for symptomatic relief; these draw significant drawbacks like poor bioavailability, low penetration of blood brain barrier, toxicity, drug interactions and adverse effects during long term therapy. Furthermore, most synthetic drugs only affect a single pathological pathway when in fact these disorders are multifactorial. [3,4]

Ayurvedic medicinal plants and phytoconstituents have attracted the interest owing to their neuroprotective and multi-target therapeutic effects. The antioxidant, anti-inflammatory, anti-cholinesterase, anti-amyloidogenic and neuroregenerative properties of bioactive compounds like curcumin, bacoside A, withanolides and ginkgolides have been reported. Such natural bioactive compounds can decrease oxidative stress, protein aggregation, restore the balance of neurotransmitters, and support the survival of neurons, without the high toxicity effects of certain synthetic ones. They have a number of poor pharmacokinetic properties, though, such as low aqueous solubility, high metabolic turnover, low gastrointestinal absorption, and insufficient permeability to the blood–brain barrier, which is known as the “bioavailability barrier” [5–9]

Advances in computational biology and computer-aided drug discovery has made it possible to quickly screen the huge pool of therapeutic molecules by molecular docking and in-silico ADMET properties. The binding affinity and interaction of the compounds with the specific neurodegenerative targets such as acetylcholinesterase (AChE), butyrylcholinesterase (BuChE), MAO-B, β-secretase and α-synuclein are evaluated through molecular docking. ADMET studies involve assessing the different pharmacokinetic and toxicity properties of the compound including absorption, metabolism, blood-brain barrier permeability and hepatotoxicity. [10,11]

This present work compares the selected ayurvedic phytoconstituents with allopathic drugs for the neurodegenerative targets by molecular docking studies and in-silico ADMET studies. The goal of the study is to determine compounds with high binding affinity, favorable PK and good safety profile and the use of computational pharmacology to integrate the traditional Ayurvedic knowledge for the development of safer and effective Neuroprotective drugs.

MATERIALS AND METHODS

Selection of Compounds

All the phytoconstituents found in Ayurvedic medicine mentioned to have a neuroprotective effect were selected along with some common allopathic drugs for comparison. The SDF files of the ligands were retrieved from the PubChem database. [12,13]

Protein and Ligand Preparation.

The structure of acetylcholinesterase (AChE) and dopamine D2 receptor (D2R) were retrieved from the Protein Data Bank (PDB). PyMOL and Discovery Studio Visualizer were used to prepare the protein, which involved removing the water molecules and minimizing the energy. Optimization of ligands and preparation in an appropriate docking format. [14–16]

Molecular Docking

The ability to bind the protein and interaction between the protein and the ligand molecule was studied by molecular docking software named AutoDock Vina. Discovery Studio Visualizer and PyMOL were used to analyze the binding energy, hydrogen bonding, hydrophobic interactions, and interacting residues. [17,18]

In-Silico ADMET Analysis

SwissADME was used to perform ADMET properties such as absorption, distribution, metabolism, excretion, blood brain barrier permeability, cytochrome P450 interactions, toxicity and drug-likeness. Oral bioavailability was estimated using Lipinski's and Veber's rules. [19,20]

Comparative Evaluation

The docking scores and ADMET properties of the phytoconstituents were compared with the standard drugs to find the compounds with good docking score, safety, and pharmacokinetic properties.

RESULTS AND DISCUSSION

Allopathic drugs have been selected and theAyurvedic phytoconstituents were docked to acetylcholinesterase (AChE, PDB ID: 4EY7) and dopamine D2 receptor (D2R, PDB ID: 6CM4) with the help of AutoDock Vina. The more negative the docking score the greater the binding affinity was. [21]

Bisnorcymserine (AChE) and Bromocriptine (D2R) exhibited the highest binding affinities with AChE (−7.6 kcal/mol) and D2R (−7.9 kcal/mol), respectively, among allopathic drugs. Regarding phytoconstituents, the one that had the highest affinity with AChE was Ginkgolide B (−8.7 kcal/mol) and the very good interaction with D2R was Withaferin A (−7.4 kcal/mol). Berberine, Piperine, Resveratrol, Curcumin and Huperzine A also had good interaction, indicating that they might have neuroprotective properties. [22–25]

SwissADME was used to carry out seven key ADMET properties assessment, namely gastrointestinal absorption, blood–brain barrier permeability, solubility, metabolism, and drug-likeness. Most allopathic drugs presented favorable pharmacokinetic parameters, while some phytoconstituents had drawbacks, such as the low solubility and BBB permeability. But Huperzine A, Berberine, Piperine, Resveratrol and 6-Gingerol had the desired ADMET property. Piperine also showed bioavailability enhancement properties. [27]

The comparative analysis revealed several phytoconstituents from Ayurveda to show docking affinities similar to or better than the typical allopathic drugs. But their only problem was in the poor pharmacokinetic optimization instead of lack of biological activity. Based on the results, phytochemicals like Ginkgolide B, Withaferin A, Huperzine A, Berberine, Piperine and Resveratrol can be used as potential lead compounds for further development of drugs to treat neurodegenerative disorders following optimization of their formulations. [23–27]

Table 1: Physicochemical and ADME Properties of Selected Allopathic Drugs

Table 2: Physicochemical and ADME Properties of Selected Ayurvedic Phytoconstituents

Table 10: Docking of Allopathic drugs with 4EY7(AChE)

Table 11: Docking of Allopathic drugs with 6CM4(DRD2)

Table 12: Docking of  Ayurvedic Phytoconstituents with 4EY7(AChE)

Table 13: Docking of Ayurvedic Phytocontituents with 6CM4(DRD2)