POTENTIAL ACTIVITY OF KAEMPFEROL AS ANTI-PARKINSON’S; MOLECULAR DOCKING AND PHARMACOPHORE MODELLING STUDY Original Article UMIL MAHFUDIN 1,2* , ANAS SUBARNAS 1 , GOFARANA WILAR 1 , FAIZAL HERMANTO 3 1 Department of Pharmacology and Clinical Pharmacy, Faculty of Pharmacy, Universitas Padjadjaran, West Java 45363, Indonesia. 2 Department of Pharmacy, Bumi Siliwangi Academic, Bandung, West Java, Indonesia. 3 Department of Pharmacology and Toxicology, Faculty of Pharmacy, Universitas Jenderal Achmad Yani, West Java 40531, Indonesia * Email: umil19001@mail.unpad.ac.id Received: 17 Jan 2023, Revised and Accepted: 14 Mar 2023 ABSTRACT Objective: This study examined molecular docking and pharmacophore modeling to evaluate the potential antiparkinson activity of Kaempferol on various types and classes of receptors. Methods: The molecular docking was performed on various classes of receptors, namely transcription factor Nrf2, A2A Adenosine, and catechol-O- methyl transferase, using auto dock 4.0.1 software. Results: Kaempferol exhibited potential effects on two of the three tests (A2A adenosine and COMT receptors) as indicated by the lowest free energy binding values (-5.42 kcal/mol,-7.16 kcal/mol, and-8.33 kcal/mol, respectively). Kaempferol also had lower inhibitory constant values on transcription factor Nrf2, A2A adenosine, and COMT receptors (106.06 µM, 5.63 µM, and 779.51 nM, respectively). Kaempferol and the natural ligand had similar functional groups according to the critical components of the interaction between amino acid residues. The pharmacophore modeling revealed that hydroxyl functional groups strongly interact with crucial amino acid residues of the receptors. Conclusion: This study concludes that kaempferol is a potential antiparkinson agent against multiple receptors. Keywords: Antiparkinson’s, Kaempferol, Molecular docking, Pharmacophore modeling © 2023 The Authors. Published by Innovare Academic Sciences Pvt Ltd. This is an open access article under the CC BY license (https://creativecommons.org/licenses/by/4.0/) DOI: https://dx.doi.org/10.22159/ijap.2023v15i3.47355. Journal homepage: https://innovareacademics.in/journals/index.php/ijap INTRODUCTION Parkinson's disease is a neurological disorder affecting 2-3% of people under 65. In Europe, the estimated prevalence and incidence rates of Parkinson's disease range from 65 to 12,500 per 100,000 and 5 to 346 per 100,000 person-years, respectively. Male gender and age are factors that contribute to the disease. Some types of pesticides and rural living have been linked to an increased incidence of Parkinson's disease. It has been observed that certain chemicals, such as 1-methyl- 4-phenyl tetrahydropyridine (MPTP) and annonacin, can lead to the death of nigrostriatal cells and a particular type of atypical parkinsonism [1]. Neuropathological indicators of Parkinson's disease include the presence of intracellular inclusions containing aggregates of alpha-synuclein and neuronal death in the substantia nigra, which leads to a deficiency of dopamine in the striatum. As the disease progresses, more cell types from the central and peripheral autonomic nervous systems become affected [2–4]. While bradykinesia and other key motor symptoms are necessary for a clinical diagnosis of Parkinson's disease, the condition is also accompanied by a range of non-motor symptoms contributing to overall disability. There are multiple pathways and mechanisms, including alpha-synuclein proteostasis, mitochondrial function, oxidative stress, calcium homeostasis, axonal transport, and neuroinflammation, involved in the underlying molecular etiology of the disease. Recent studies on diagnostic biomarkers have benefited from neuroimaging techniques such as positron emission tomography (PET), single photon emission computed tomography (SPECT), and advanced magnetic resonance imaging (MRI) as they enable early and differential diagnosis. Parkinson's disease is primarily pharmacologically treated by replacing striatal dopamine, non-dopaminergic methods to address motor and non-motor symptoms, and deep brain stimulation for those experiencing untreatable L-DOPA-related motor problems. Alpha-synuclein aggregation and cellular transit have been potential therapeutic targets in experimental therapies that restore striatal dopamine. It is challenging to identify the markers of prodromal stages of the disease, which would allow for the early implementation of disease- modifying treatments. Currently, there are no disease-modifying treatments for Parkinson's disease, and treatment options are largely focused on managing symptoms and targeting the dopaminergic pathway. The most effective medication for motor symptoms is levodopa, the gold standard for treating Parkinson's. The remaining dopaminergic neurons in the substantia nigra convert levodopa to dopamine once it has crossed the blood-brain barrier. Levodopa is usually administered as tablets multiple times daily, but in advanced cases, it can also be given through duodenal infusion. The medicine significantly reduces the symptoms and supports a diagnosis of Parkinson's disease through a pharmacological test. Decarboxylase inhibitors, such as carbidopa or benserazide, can reduce levodopa's peripheral dopaminergic side effects, such as nausea and hypotension [5, 6]. Other side effects of levodopa include drowsiness, confusion, hallucinations, and impulse control disorders (ICDs), such as hypersexuality, compulsive shopping, gambling, and punding. However, developing motor problems, such as fluctuations, dyskinesia, dystonia, and wearing off, is a major limitation of levodopa [7]. Researchers have explored the use of a novel alternative for the treatment of Parkinson's disease that is derived from a secondary metabolite called Kaempferol to address the negative effects associated with standard levodopa therapy. Kaempferol is a common secondary metabolite found in plants with pharmacological properties such as antibacterial, antifungal, antiplasmodial cytogenetic, antiulcerogenic, antioxidant, antiviral, antiprotozoal, anti-colon cancer, and cytotoxic activity [8]. However, the literature on kaempferol's phytochemical makeup and biological effects is limited. Hence, it is necessary to examine kaempferol's bioactivity and pharmacological properties. In this study, a molecular docking study was performed to assess the activity of kaempferol as an antiparkinsonian agent using structure- based drug design and pharmacophore modeling. This study explains the molecular basis of kaempferol's potential as a treatment for Parkinson's disease MATERIALS AND METHODS Identification of target receptors and the lead compounds To identify the targets for this study, receptors commonly used to assess anti-parkinsonian effects, such as catechol-O- International Journal of Applied Pharmaceutics ISSN- 0975-7058 Vol 15, Issue 3, 2023