Inhibitory Potential of Phyto-Constituents from Sorghum Stem on Neuro-modulatory Enzymes: A Computational Approach

Damilola A Omoboyowa^1*, Toheeb A Balogunand¹ and Oluwatosin A Saibu^2
*Correspondence: Damilola A Omoboyowa, Department of Biochemistry, Adekunle Ajasin University, Akungba-Akoko, Ondo State, Nigeria, Tel: + 2347032665874, Email:

Keywords

Cholinesterase • Monoamine oxidase • Phyto-constituents • Sorghum • Quercetin

Introduction

Neurodegenerative disorders are diseases of the central and peripheral nervous system, associated with protein aggregation and inflammation as well as oxidant generation in the central nervous system (CNS) [1]. These disorders includes: Alzheimer disease, brain tumors, Parkinson’s disease, epilepsy etc. Various neurological disorders possess common features at cellular and subcellular biological events including the synthesis of new structural and functional protein molecules at the cytosol and endoplasmic reticulum [1]. Insufficient synthesis of neurotransmitters and breaking down of chemical messengers in the synaptic cleft resulting from higher activity of neuronal enzymes such as cholinesterase and monoamine oxidases lead to low concentration of this neurotransmitter which has been linked with cognitive abnormalities [2], since high activity of these enzymes has been attributed to be part of the biological mechanisms associated with neurodegenerative disorders [1].

Cholinesterase including acetylcholineseterase (Ache) and bytyrylcholinesterase (Bche) are involved in the hydrolysis of acetylcholine in the synaptic region while monoamine oxidases (MAOs) are involved in the oxidative deamination of endogenous monoamines neurotransmitter; this enzyme is involve in the deamination of biogenic amines and is present in the CNS and PNS tissues [3]. Neurotransmission by biogenic monoamines is involved in brain functions. These amines balance utilizes the enzyme in neuronal and glial cells. Inhibition of this enzyme, increases monoamines concentration in the synaptic cleft [4].

Synthetic drugs targeting Ache/Bche and MOA are used for the management of neurodegenerative disorders; they are not without side effects such as hepatotoxicity, gastrointestinal disorders, dizziness, diarrhea, vomiting, nausea and pharmacokinetics disadvantages [5,6]. Hence, investigation of natural compounds with Ache/Bche and MAO inhibition potentials used in traditional management of neurological disorders has been the means of searching for new drugs that will liberate human race from these life-threatening disorders.

Sorghum (Sorghum color) is a genus of flowering plants in the family Poaceae, it is one of the most cultivated plants in the world [7]. Antioxidants and bioactive chemicals are abundant in sorghum grains [8]. The stem of the plant has been involved in herbal medicine for management of anaemia and malaria [9]. The sorghum stem extract has been reported to modulate acetylcholinesterase activities [7]. Oboh et al. [7] reported the phenolic compounds present in sorghum stem which might contribute to the Ache/ Bche and MAO inhibitory activities of the plant. However, screening such large number of drug candidates may not be possible due to cost both in term of money and time. Application of bioinformatics tools such as molecular docking may lead to development of neuro-modulatory compounds with Ache/Bche and MAO inhibitory activities. The present study is aimed to determine the molecular interaction of prostigmine and ten (10) phyto-compounds from sorghum stem with Ache/Bche and MAO target enzymes for neurodegenerative drugs. A picture of Sorghum is shown in Figures 1 and 2.

Materials and Methods

Ligands preparation

Ten (10) characterized phyto-compounds from sorghum stem used in this study were obtained from Oboh et al. [7]. The compounds were used in the production of compound library downloaded from NCBI PUBCHEM database (www.ncbi.nlm.nih.gov/pccompound) in 2D format. The phyto-compounds and prostigmine were prepared according to David et al. [10].

Protein preparation

Crystallized 3D structure of the target proteins; acetylcholinesterase, butyrylcholinesterase and monoamine oxidase were downloaded from protein data bank (http://www.rcsb.org/pdb/home.do). The 3D structures were viewed with maestro 11.5 interface and prepared with wizard at pH 6 ± 1. Water molecules and other interfering ligands were deleted from the protein.

Receptor grid generation

The area of interaction between the proteins and ligands were generated with receptor grid generation tool in maestro 11.5 which is the area around the binding pocket in term of co-ordinates x, y and z.

Molecular docking using glide

Molecular docking was carried out using glide tool on maestro 11.5 according to Schrodinger Release 2017-1. The Ligands library (Phytocompounds) were docked into the binding site of the proteins according to standard precision algorithm with the ligand sampling treated as flexible. The ligands interaction tool was used to view the interaction diagram of the ligands with the residues at the binding site of the proteins [11].

ADME toxicity screening

The ligands were subjected to absorption, distribution, metabolism, excretion screening using the Qikprop tool on maestro 11.5 according to Schrodinger Release [12].

Conclusion

From the in silico study, phyto-compounds from sorghum stem could be potential inhibitor of Ache/Bche and MAO proteins. These phyto-compounds showed better molecular interaction than the standard ligand (prostigmine) via hydrogen bond and pi-pi stacking. These results depicted new insight into the therapeutic use of sorghum for the management of neurodegenerative disorders.

Acknowledgements

The Authors wish to acknowledge Adelakun N.S. of Center for Bioinformatics and Drug Discovery, Adekunle Ajasin University, Akungba- Akoko, Ondo State for providing the software for the analysis.

Conflict of Interest

The authors declare no conflict of interest.

References

1. Rasool, Mahmood, Arif Malik, and Muhammad Saeed Qureshi, et al. "Recent updates in the treatment of neurodegenerative disorders using natural compounds." Evid-Based Compl Alternat Med (2014).
2. Felder, Christian C, Frank P Bymaster, and John Ward, et al. "Therapeutic opportunities for muscarinic receptors in the central nervous system." J Med Chem 43 (2000): 4333-4353.
3. Delumeau, JC, D Bentue-Ferrer, and JM Gandon, et al. "Monoamine oxidase inhibitors, cognitive functions and neurodegenerative diseases." In Amine Oxidases: Funct Dysfunct, Springer, Vienna, (1994): pp: 259-266.
4. Riederer, Peter, and Thomas Müller. "Use of monoamine oxidase inhibitors in chronic neurodegeneration." Exp Opin Drug Metabol Toxicol 13 (2017): 233-240.
5. dos Santos Pisoni, Diego, Jessie Sobieski da Costa, and Douglas Gamba, et al. "Synthesis and AChE inhibitory activity of new chiral tetrahydroacridine analogues from terpenic cyclanones." Europ J Med Chem 45 (2010): 526-535.
6. Seniya, Chandrabhan, Ghulam Jilani Khan, and Kuldeep Uchadia. "Identification of potential herbal inhibitor of acetylcholinesterase associated Alzheimer’s disorders using molecular docking and molecular dynamics simulation." Biochem Res Intern (2014).
7. Oboh, Ganiyu, Taiwo M Adewuni, and Ayokunle O Ademosun, et al. "Sorghum stem extract modulates Na+/K+-ATPase, ecto-5′-nucleotidase, and acetylcholinesterase activities." Comparat Clin Pathol 25 (2016): 749-756.
8. Taylor, John RN, Peter S Belton, and Trust Beta, et al. "Increasing the utilisation of sorghum, millets and pseudocereals: Developments in the science of their phenolic phytochemicals, biofortification and protein functionality." J Cereal Sci 59 (2014): 257-275.
9. Ilori, Olukemi O, and Olukemi A Odukoya. "Hibiscus sabdarifa and Sorghum bicolor as natural colorants." Electron J Environ Agric Food Chem 4 (2005): 858-862.
10. David, Temitope I, Niyi S Adelakun, and Olaposi I Omotuyi, et al. "Molecular docking analysis of phyto-constituents from Cannabis sativa with pfDHFR." Bioinformat 14 (2018): 574.
11. Balogun TA, Omoboyowa DA, and Saibu OA. “In silico anti-malaria activity of quinolone compounds against Plasmodium falciparum Dihydrofolate Reductase (pfDHFR).” Internat J Biochem Res Rev 29 (2020): 10-17.
12. Schrödinger, L. "Release 2017–1: Lig Prep." LLC, New York, NY: Schrödinger, USA, (2017).
13. Joshi CK, Joshi HK. “Molecular docking analysis of acetylcholinesterase withphytocompounds from medicinal plants.” Multilogic in Science (2015), pp: 164-168.
14. Pagadala, Nataraj S, Khajamohiddin Syed, and Jack Tuszynski. "Software for molecular docking: a review." Biophys Rev 9 (2017): 91-102.
15. Srikanth JI, Kavimani S, and Uma M. “Comparative molecular docking study of phytoconstituents identified in Morinda citrifolia Linn on acetylcholinesterase and butyrylcholinesterase.” J Chem Pharmaceut Res 9 (2017): 121-125.
16. Wilkinson, Anthony J, Alan R Fersht, and David M Blow, et al. "Site-directed mutagenesis as a probe of enzyme structure and catalysis: tyrosyl-tRNA synthetase cysteine-35 to glycine-35 mutation." Biochem 22, no. 15 (1983): 3581-3586.
17. Cosmas, S, PE Joshua, and OA Durojaye. "In-silico Structure-Activity Relationship and Molecular Docking Studies of Monosubstitted 6-Gingerol against Streptococcus pneumoniae Phosphomevalonate Kinase." Internat J Sci Eng Res 9 (2018): 1733-1742.