Asiatic Acid,Quercetin,and Kaempferol From Centella asiatica as Potential Inhibitors of Alpha-1-Antichymotrypsin in Alzheimer's Disease

Abstract

Selected compounds from Centella asiatica with proven neuroprotective potential and analyzed strong binding affinity with molecular docking can be considered as potential inhibitors for alpha-1-antichymotrypsin in Alzheimer's disease.

The “Dementia in India” report published by the Alzheimer's and Related Disorders Society of India (ARDSI) in 2020 estimates that around 5.3 million Indian citizens over the age of 60 suffer from dementia currently, the most common cause for this being Alzheimer's disease (AD). ¹ The estimated dementia prevalence for adults ages 60+ in India is 7.4%. Conventional treatment mostly includes cholinesterase inhibitors and NMDA receptor antagonists. Side-effect associated with currently available therapeutics is justification enough for exploring alternative therapeutic interventions from traditional medicinal system.

Centella asiatica (CA) is quite reputed in traditional medicine for the treatment of cognitive deficiencies. Studies have shown that this plant extract and its key components exhibit a range of anti-inflammatory, neuroprotective and cognitive benefits. As mitochondrial dysfunction and oxidative stress are key players in neurodegenerative disease, mitoprotective and antioxidative effects of CA make it a strong candidate for use as an anti-AD formula. ² Studies have shown that alpha-1-antichymotrypsin (AACT), an acute phase serum glycoprotein accumulates abnormally in the brain of AD patients and promote aggregation of amyloid-β plaques. ³

AACT plays a pivotal role in the pathogenesis of AD and can be used as a potential therapeutic target for anti-AD drugs. In molecular docking study, we have attempted to find potential ligands with proven neuroprotective potential to inhibit the activity of AACT.

Crystal structure of AACT (6HGH) was retrieved from Protein Data Bank (PDB). UCSF CHIMERA Software was used for preparing protein for molecular docking. Active compounds present in CA were obtained from IMPPAT database. ADME-related properties, namely, oral bioavailability (OB), drug likeness (QED), blood-brain barrier (BBB) penetration, number of Lipinski's rule violations, and gastrointestinal absorption were evaluated to assess the compounds for their ability to become potential drug candidates. Substances with OB ≥ 30%, QED ≥ 0.18, high GI absorption, and 0 Lipinski's rules violations were chosen for the study. After filtering asiatic acid, kaempferol, □-bisabolene, linalool, and quercetin were selected for docking. Docking of AACT with selected ligands was performed with Vina wizard plug-in of PyRx and binding affinities of the ligands towards AACT were obtained. BIOVIA Discovery Studio Visualizer was used to analyze amino-acid residues involved in the binding. ADME-related parameter values for the chosen ligands along with docking analysis are presented in Table 1. Asiatic acid, quercetin, and kaempferol exhibited excellent binding with AACT. Asiatic acid, which has a binding affinity of −8.6 kCal/mol, mostly interacted with the residues in binding pocket AACT. Quercetin and kaempferol showed a binding affinity of −7 kCal/mol and were involved with mostly the same residues of binding pocket. □-bisabolene and Linalool showed weak binding affinities (−5.4 and −4.5 kCal/mol, respectively) hence not continued for further analysis.

Table 1.

ADMET-Related Parameter Values Along With Docking Results of Selected Compounds.

Asiatic acid and its derivatives exert protective effects against cytotoxicity in the neuronal cell lines exposed to neurotoxic compounds like glutamate, methamphetamine, and AlCl₃. Asiatic acid also has shown beneficial effects against cognitive impairments induced in animal models. ⁴ Kaempferol and its derivatives have shown definite neuroprotective role by preventing deposition of amyloid fibrils, inhibiting microglial activation, reducing inflammation, preventing oxidative stress and inhibiting cholinesterase activities. ⁵ Neuroprotective effects of quercetin have been demonstrated in many animal experiments and human trials. It protects the organism against neurotoxic chemicals and also can prevent progressive neuronal injury and neurodegeneration. ⁶

Selected compounds from CA with proven neuroprotective potential and analyzed strong binding affinity with molecular docking can be considered as potential inhibitors for AACT in AD. Appropriate clinical trial experiments can be designed to validate their potential as drug candidates.