TITLE: DRUG REPURPOSING FOR PARKINSON’S DISEASE USING MORGAN FINGERPRINTING AND MOLECULAR DOCKING: IDENTIFICATION OF CARBIDOPA, A DOPA DECARBOXYLASE INHIBITOR, AS A POTENTIAL ALTERNATIVE TO LEVODOPA
AUTHOR(S):Mr. Jagdish S. Belekar*,Mr. Adarsh J. Bhutal , Mr. Pritam B. Mane, Mr. Sukesh R. Pandhare, Mr. Sairaj B.Bhat
Abstract:
Parkinson's disease (PD) is a progressive neurodegenerative disorder characterized by the loss of dopaminergic neurons, leading to motor and non-motor dysfunctions. Levodopa, the gold-standard therapy, often results in diminished efficacy and motor fluctuations with long-term use, highlighting the need for alternative treatments. This study employed computational drug repurposing to identify potential therapeutic candidates for PD, focusing on the Dopamine D₂ receptor, a key target in PD pathophysiology. Using Morgan fingerprint-based virtual screening and molecular docking, 19 structurally similar compounds to Levodopa were identified. Carbidopa, a DOPA decarboxylase inhibitor, exhibited the highest binding affinity (–6.4 kcal/mol) and was identified as a promising repurposing candidate. The results underscore the potential of Carbidopa as an adjunctive or alternative treatment for PD, offering enhanced therapeutic efficacy with its favorable interaction profile. The study demonstrates the utility of computational methods in drug discovery, enabling the identification of existing drugs with new therapeutic roles.
Keywords:
Parkinson's Disease, Drug Repurposing, Dopamine D₂ Receptor, Molecular Docking, Carbidopa.
Introduction:
Parkinson’s disease (PD) is a progressive neurodegenerative disorder characterized by the selective loss of dopaminergic neurons in the substantia nigra pars compacta, leading to dopamine deficiency in the striatum and resulting in classical motor symptoms such as bradykinesia, rigidity, resting tremor, and postural instability¹. In addition to motor dysfunction, PD is often associated with non-motor manifestations including cognitive impairment, mood disorders, and autonomic dysfunction, reflecting widespread neurochemical alterations².
Despite extensive research, current pharmacotherapeutic strategies for PD remain primarily symptomatic. Levodopa, a dopamine precursor, continues to serve as the gold-standard treatment due to its ability to replenish striatal dopamine levels. However, long-term Levodopa therapy is associated with motor fluctuations, dyskinesias, and diminished efficacy over time. Adjunctive therapies such as dopamine agonists and monoamine oxidase-B (MAO-B) inhibitors offer temporary benefits but fail to halt disease progression3. Consequently, the identification of alternative or adjunctive agents with enhanced efficacy and safety profiles remains an urgent therapeutic priority.
The Dopamine D₂ receptor (PDB ID: 1I1R), a G protein–coupled receptor (GPCR), plays a pivotal role in regulating dopaminergic neurotransmission, motor control, and neuroplasticity4. Dysregulation of D₂ receptor signaling has been implicated in the pathophysiology of PD, making it an attractive molecular target for drug discovery.
In this context, computational drug repurposing has emerged as a powerful approach to accelerate the identification of novel therapeutic candidates from existing drug libraries. By integrating cheminformatics and molecular docking, this strategy minimizes cost, time, and clinical risk compared to traditional de novo drug discovery. Among various methods, Morgan fingerprint–based virtual screening enables recognition of structural and pharmacophoric similarities between known drugs and potential analogs5.
In the present study, Morgan fingerprint–based virtual screening was conducted using Levodopa as the lead compound against a comprehensive drug database, followed by molecular docking analysis against the Dopamine D₂ receptor. The screening identified 19 structurally similar compounds, among which Carbidopa, a well-known DOPA decarboxylase inhibitor, exhibited the highest binding affinity (–6.4 kcal/mol) compared to Levodopa (–5.8 kcal/mol). Carbidopa’s favorable interaction profile and pharmacodynamic synergy with Levodopa suggest its potential as an effective alternative or adjunctive therapeutic candidate for PD management.
This investigation underscores the utility of computational drug repurposing in uncovering novel therapeutic roles of existing drugs. The findings highlight Carbidopa’s strong binding affinity and target specificity toward the Dopamine D₂ receptor, paving the way for further in vitro and in vivo validation to substantiate its role as a potential alternative treatment in Parkinson’s disease.
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