In the 21st century, computer-aided drug design (CADD) enables a better understanding of synthetic protocols that provide the opportunity to transform drug development towards developing novel drugs with superior clinical properties. In this regard, many repurposed drugs have been developed using computational approaches and approved by FDA at a faster quicker approach to the clinical trials to treat several diseases such as inflammation, hypertension, obesity, type-2 diabetes, and Alzheimer’s disease (Figure 1) [1, 2]. The CADD approach further helps assess whether natural products/phytoconstituents cope with biological activity . Natural products contain a range of phytochemical classes such as indole, quinolizidine, isoquinoline, stilbenes, piperidine, phenolics, flavonoids, and terpenoids [4-6], which have profound effects to exhibit excellent eco-friendly therapeutic potential along with better biodegradation with high environmental compatibility possessing the excellent bioactive functionalities owing to their core moieties .
Figure 1. Some FDA-approved drugs to treat Alzheimer's disease and diabetes type II
Turmeric (Curcuma longa), often used as a spice and affects the nature, color, and taste of foods, under the family Zingiberaceae, is commonly called turmeric or Haldi, typically cultivated and propagated in the tropical part of Asia, including India, China, Thailand, Iran, Malaysia, etc. The chief medicinally important part is its rhizome which contains curcuminoids, phenolics, aromatic quinone, quinines, and other bioactive compounds. The extract of Haldi is traditionally known for its therapeutic and biological engagements, for example, antioxidant, cardiovascular diseases, diabetic, immune-boosting, anti-inflammatory, anticancer, etc. Turmerones, the principal sesquiterpenes occurred naturally in turmeric, are α-turmerone, aromatic-turmerone, and β-turmerone, out of which Ar-turmerone is a major bioactive phytoconstituent . Ar-turmerone is one of the main compounds contained in turmeric essential oil. Ar-turmerone also has diverse biological activities, as well as curcumin. Hucklenbroich et al. reported that Ar-turmerone inhibited microglia activation indicating its effectiveness in treating neurodegenerative diseases . In a previous study, we found that curcuminoids and other turmeric constituents had significant in silico ADME and COX-2 inhibitory activity . Ar-turmerone has powerful antivenom action against snake bites . Likewise, Ar-turmerone has anti-inflammatory, anti-aging, anti-plasmodial, and neuroprotective activities [12-14]. In addition, with a certain dose, ar-turmerone has biological activities such as antiepileptic, antidepressant, anti-dermatophyte, anticancer, and antiplatelet effects . Various biological action of ar-turmerone has led to the development of research on ar-turmerone.
In continuation, we investigated Ar-Turmerone (Ar-Tume) for Acetylcholine Esterase (AChE) inhibition and antidiabetic target as a natural product-based emerging scaffold.
Materials and methods
Preparation of receptor human Alzheimer’s disease inhibitors and ligands
The crystal structure of human anticholinesterase (AChE) inhibitor (4PQE) under a resolution of 2.90 Å and the crystal structure of human salivary alpha-Amylase dimer (1XV8) hydrolase inhibitor under a resolution of 3.00 Å in PDB format was downloaded from Protein Data Bank (https://www.rcsb.org/). Galantamine (Gala, ChemSpider ID: 9272) and Voglibose (Vogl, ChemSpider ID: 392046) were taken from ChemSpider online platform (http://www.chemspider.com/) as a standard reference drugs. Ligands 1-3 (Table 1) were prepared using ChemDraw Ultra (Cambridge Soft Corporation USA) and obtained SMILES and .mol2 files were validated via Avogadro Software v1.2.0.
Table 1. Selected reference drugs and Ar-Tumeroneas ligand
Biological characteristics evaluation and ADMET profile assay
Molinspiration biological characteristics of the selected compounds 1-3 were evaluated using Molinspiration Cheminformatics Online Server (https://www.molinspiration.com/) . To evaluate ADMET properties, Swiss ADME algorithm (http://www.swissadme.ch) and pkCSM online servers (http://biosig.unimelb.edu.au/pkcsm/) were used.
Molecular docking studies against human anticholinesterase and antidiabetic hydrolase inhibitors
The Vinadock automation-assisted prediction of binding energies and interactive 3D visualization of results towards human anticholinesterase (AChE) inhibitor (4PQE: water molecules were deleted from the uploaded protein structure before docking) was used CB-Dock Online platform; server2 (http://cadd.labshare.cn/cb-dock2/) [10,17] concerning reference drugs.
Results and Discussion
Biological characteristics evaluation and prediction of ADMET properties
The biological activities of Gala, Vogl, and Ar-Tume were evaluated and presented in Table 2. Concerning the standard drug, Ar-Tume has shown the pronounced biological action profiles. For a novel drug discovery using pharmacokinetic and pharmacodynamics profiles, the validation of the drug is essentially recommended by researchers . Therefore, it fundamentally required the safety criterion with significant efficacy [10,18].
Table 2. Molinspiration-predicted biological characteristics of selected drugs
The ADMET profiles for Gala, Vogl, and Ar-Tumehave been found to have significant positive characteristics concerning physicochemical properties, lipophilicity, drug-likeness, and medicinal chemistry parameters (Table 3) for targeted drugs calculated with Swissdock ADME and pkCSM platforms capped with biological-logarithms. Ar-Tume exhibited remarked performance and characteristics to a significant extent, similar to standard drugs. Table 4 lists that Ar-Tume shows acceptable absorption parameters compared with the reference drug concerning Caco-2 permeability, Caco-2 permeability, human intestinal absorption, and skin permeability. Furthermore, Table 5 provides considerable human volume of distribution and human fraction unbound (Fu) values, BBB, and CNS permeability for Ar-Tume. Table 6 also explains that Ar-Tumeexhibitedgood effectiveness towards CYP2D6 substrate, CYP3A4 substrate, CYP1A2 inhibitor, CYP2C19 inhibitor, CYP2C9 inhibitor, CYP2D6 inhibitor, and CYP3A4 inhibitor. Table 7 demonstrates non-hepatotoxic, and no toxicity profiling was observed for Ar-Tume.
Table 3. Physicochemical properties, lipophilicity, drug-likeness, and medicinal chemistry parameters for selected drugs calculated with Swissdock ADME and pkCSM
Table 4. Absorption parameters for selected drugs calculated with pkCSM
Table 5. Distribution and excretion parameters for selected drugs calculated with pkCSM
Table 6. Metabolism parameters for selected drugs calculated with pkCSM
Table 7. Toxicity parameters for selected drugs calculated with pkCSM
Molecular docking studies
Molecular docking is used to predict the orientation, type of interaction, and binding energy of selected molecular ligands in the interior of the binding site. Figure 2 depicts the docking score for the active linkage of Gala, Vogl, and Ar-Tume against human anticholinesterase (AChE) inhibitor (4PQE) and human salivary alpha-Amylase dimer (1XV8) hydrolase inhibitor (Table 1) and as a result, the binding energies directs a significant ratio concerning the reference drug (Table 1, Figures 2 and 3). Plant-derived natural products are potentially important because of their inherent biological activities like antioxidant, antimicrobial, antidiabetic, etc. with environmental compatibility [15-17, 19, 20]. This study demonstrates that the selected compound Ar-Tume remarked to have mobile superior docking scores/negative binding energies concerning the reference drugs attributed to the strong hydrogen-bonding interactions in both inter and intra assemblies towards both anti-Alzheimers and antidiabetic capabilities.
Figure 2. A comparative molecular docking score of Gala, Vogl, and Ar-Tume compounds
Figure 3. Molecular docking pattern of Gala, Vogland Ar-Tume ligands
Turmeric contains various natural phytoconstituents and has been found effective to have biological and therapeutic potential such as antimicrobial, anticancer, antidiabetic, and other health-related ailments. In the present study, Ar-Turmerone, one of the chief phytoconstituents present in Curcuma longa for human anticholinesterase (AChE) inhibitor (4PQE) and human salivary alpha-Amylase dimer (1XV8) hydrolase inhibitor as an emerging scaffold. This study reveals that the selected compound Ar-Tume showed remarked biological, ADMET profiling, and superior docking scores/ negative binding energies (-7.9 against 4PQE and -6.7 against 1XV8) concerning the reference drugs attributed to the strong hydrogen-bonding interactions both inter and intra assemblies towards both anti-Alzheimer's and antidiabetic capabilities which might further be used as oral therapeutics after clinical trials and these derivatives would be the initial step towards the exploration for biomedical applications with promising drug candidature to support in the treatment of neurologic disorders and diabetes in future.
Prof. S. A. Ahmed, Vice-Chancellor of Glocal University, is acknowledged for his moral support and critical suggestions.
Shafat Ahmad Khan:
Citation M. Yusuf, S. Pal, M. Shahid, M. Asif*, S. Ahmad Khan, R. Tyagi. Docking and ADMET Study of Ar-Turmerone: Emerging Scaffold for Acetylcholine Esterase Inhibition and Antidiabetic Target. J. Appl. Organomet. Chem., 2023, 3(1), 52-60.