FROM DOCKING TO DYNAMICS: REPURPOSING FDA-APPROVED DRUGS AS USP13 INHIBITORS FOR PARKINSON'S DISEASE

Abstract

The aggregate term neurodegenerative diseases (NDD) refer to a group of conditions typified by a slow and steady decline in the structure and functionality of the nervous system. These disorders affect a large proportion of the world's population. They severely impair both motor and non-motor skills. One typical example of such an illness is Parkinson's disease (PD). It is classified as dominant NDD. It typically affects those over 65. Degeneration of dopamine-producing neurons in the Substantia Nigra par compacta (SNpc) a particular area of the brain important for regulating a variety of symptoms, including bradykinesia postural instability, stiffness and tremors is one prominent sign of PD. Lewy bodies are a major pathogenic feature of PD and they are present in dopaminergic neurons. The primary component of those bodies is alpha synuclein a protein that causes aberrant buildup and impairs nerve cell function in pathological situations. There is currently no proven treatment for PD. Despite several experimental efforts, no cure exists. The mainstay of current therapy is L-dopa. It acts by increasing brain dopamine levels to alleviate symptoms. This approach highlights the urgent need for novel curative methods. Yet it does not permanently halt the illness from progressing. The current study investigates Ubiquitin-Specific Protease 13's (USP13) potential for treatment in this regard. USP13 is classified as a deubiquitinase It plays an essential role in the ubiquitin-proteasome system. The system disrupts malformed and damaged proteins. In PD USP13 prevents the precise decline of alpha synuclein by removing ubiquitin tag, thus preventing its degradation and leading to the accumulation of undesirable protein groups. The imbalance in protein level is harmful. This is especially true in the dopaminergic neurons which worsens the neurodegenerative condition. Due to the significant role of USP13 in PD, concentrating on this enzyme provides a novel way of treating this condition. To rapidly identify a possible inhibitor of USP13, the study uses a drug repositioning method using an FDA-approved medicinal product. Drug repositioning is an efficient and economical strategy involving the repositioning of an existing medicinal product for new healthcare purposes. This technique exploits the significant safety and pharmacokinetic properties of the above-mentioned medicinal product, which contributes to speeding up the process of developing new medicines. Sophisticated pharmacoinformatic tools were used to examine the selection of FDA-approved medicines to see if they could block USP13. The method uses computational techniques to predict the method by which a substance could sufficiently bind to the USP13 enzyme. Canrenone has been identified as a candidate for the capability of favourably binding USP13. Canrenone is considered to be an aldosterone antagonist and was designed to have beneficial pharmacokinetic and pharmacodynamic properties, as well as the ability to penetrate the blood brain barrier, which is essential vi for a drug designed to treat neurodegenerative disorders. Canrenone's promise was further confirmed by examination using the forecasting PASS study and MD simulation. The PASS investigation revealed Canrenone's numerous physiological activities, which contributed to its potential for curative use. To assess the stability and robustness of the Canrenone's interaction with USP13, an MD simulation was used. The findings suggest that Canrenone, as opposed to the currently available USP13 inhibitor Spautin-1, has a higher binding affinity to USP13. Canrenone could be a better PD therapy. In conclusion, using usp13 as a target for the treatment of PD is highlighted by this work. The research proposes Canrenone as a potential USP13 inhibitor which exhibits higher efficiency and constructive pharmacokinetic properties when used in combination with an already approved medicinal product. To accelerate the introduction of a new treatment for PD, the investigation uses a unique method of integration of docking, PASS investigation, as well as MD simulation. That analysis shows significant progress in the search for improved treatment in the fight against the disabling effects of PD as well as in improving the welfare of people affected by the current NDD.