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Pharmacophore modelling and molecular dynamics simulation to identify novel molecules targeting catechol-O-methyltransferase and dopamine D3 receptor to combat Parkinson’s disease

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Abstract

Parkinson’s disease is a neurological illness that slowly impairs a small number of neurons in the substantia nigra, a part of the brain. Dopamine, a substance (neurotransmitter) that disseminates signals to different regions of the brain and, when it functions correctly, coordinates smooth and balanced muscular activity, is typically produced by these cells. One-hand tremor is frequently the first sign of Parkinson’s disease. Loss of balance, stiffness, and delayed mobility are further symptoms. Proteins including catechol-O-methyltransferase and dopamine D3 receptors were taken into consideration as prospective therapeutic targets in this study. Two ligand-based pharmacophore models were generated with the help of compounds used for Parkinson’s disease which have structural similarity, screened from the first 16 compounds found in the drug bank. In the second case, 9 compounds that have similar structure to the compound istradefylline were selected. Based on docking score, intermolecular interactions, ADME (absorption, distribution, metabolism, and excretion) features, pharmacophore, and toxicity investigations, the inhibitors among the chosen compounds were found. Additionally, the chosen inhibitor underwent a 100 nanosecond molecular dynamics simulation with the two protein targets to determine its stability and binding affinity. The compound 3,4-Bis(1,3,5,6-heptatetraenyloxy) benzaldehyde was identified to be the most promising lead molecule in this analysis due to its better binding affinity, better pharmacophore properties, and greater stability. Hence, by targeting both specified proteins, the compound 3,4-Bis(1,3,5,6-heptatetraenyloxy) benzaldehyde should be beneficial against Parkinson’s disease.

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The authors did not receive support from any organization for the submitted work.

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Authors and Affiliations

  1. Biotechnology Department, Sahrdaya College of Engineering and Technology, Kodakara, Thrissur, Kerala, 680684, India

    Amitha Joy, Sidharth Menon, Neethu Mariam Thomas, Meha Christy, Aiswarya D. Menon & Arun John

  2. Department of Molecular Analytics, Saveetha School of Engineering, Chennai, Tamilnadu, 602105, India

    Sidharth Menon, Neethu Mariam Thomas, Meha Christy, Aiswarya D. Menon & Arun John

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  1. Amitha Joy
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Contributions

All authors contributed to the study conception and design. Material preparation, and data collection and analysis were performed by AJ, SM, NMT, MC, ADM, and AJ. The first draft of the manuscript was written by NMT and SM, and all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.

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Correspondence to Amitha Joy.

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Joy, A., Menon, S., Thomas, N.M. et al. Pharmacophore modelling and molecular dynamics simulation to identify novel molecules targeting catechol-O-methyltransferase and dopamine D3 receptor to combat Parkinson’s disease. Polym. Bull. (2023). https://doi.org/10.1007/s00289-023-05087-8

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  • DOI: https://doi.org/10.1007/s00289-023-05087-8

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