Alzheimer’s disease (AD) is the most prevalent form of dementia and represents one of the highest unmet requirements in medicine today. There is shortage of novel molecules entering into market because of poor pharmacokinetic properties and safety issues. Drug repurposing offers an opportunity to reinvigorate the slowing drug discovery process by finding new uses for existing drugs. The major advantage of the drug repurposing approach is that the safety issues are already investigated in the clinical trials and the drugs are commercially available in the marketplace. As this approach provides an effective solution to hasten the process of providing new alternative drugs for AD, the current study shows the molecular interaction of already known antipsychotic drugs with the different protein targets implicated in AD using in silico studies. A computational method based on ligand–protein interaction was adopted in present study to explore potential antipsychotic drugs for the treatment of AD. The screening of approximately 150 antipsychotic drugs was performed on five major protein targets (AChE, BuChE, BACE 1, MAO and NMDA) by molecular docking. In this study, for each protein target, the best drug was identified on the basis of dock score and glide energy. The top hits were then compared with the already known inhibitor of the respective proteins. Some of the drugs showed relatively better docking score and binding energies as compared to the already known inhibitors of the respective targets. Molecular descriptors like molecular weight, number of hydrogen bond donors, acceptors, predicted octanol/water partition coefficient and percentage human oral absorption were also analysed to determine the in silico ADME properties of these drugs and all were found in the acceptable range and follows Lipinski’s rule. The present study have led to unravel the potential of leading antipsychotic drugs such as pimozide, bromperidol, melperone, anisoperidone, benperidol and anisopirol against multiple targets associated with AD. Benperidol was found to be the best candidate drug interacting with different target proteins involved in AD.

Alzheimer’s disease (AD) is a multifactorial disorder characterized by exponential loss of memory and cognitive deficit involving several disease modifying targets (amyloid beta, beta-secretase, monoaminoxidase-B, and cholinesterase). The present study explores multi-target directed ligand approach using secondary metabolite reserpine (RES) and ajmalicine (AJM) obtained from Rauwolfia serpentina roots. Novel LCMS and HPLC methods were developed for identification and quantification of reserpine and ajmalicine. In vitro enzyme inhibition assays were performed to evaluate anti-cholinesterase, β-site amyloid cleaving enzyme (BACE-1) inhibition and monoamine oxidase-B (MAO-B) inhibition, further analyzed with in silico analysis. Anti-amyloidogenic potential was studied using anti-aggregation studies along with TEM and circular dichroism (CD) analysis. In vitro neuroprotective potential against Aβ toxicity and anti-oxidative stress was demonstrated using PC12 cell cultures. Reserpine is a more potent dual cholinesterase inhibitor than ajmalicine (IC₅₀ values of 1.7 μM (AChE) and 2.8 μM (BuChE)). The anti-aggregation activity of reserpine (68%) was more than ajmalicine (56%). Both compounds demonstrated neuroprotective activity against Aβ42 (92%) and H₂O₂ (93%) induced toxicity in PC12 cells against controls. Phytocompounds also inhibited MAO-B and BACE-1 enzymes in concentration dependent manner. Molecular docking studies indicated the strong binding of compounds to the catalytic site of targets. This novel study demonstrated that reserpine and ajmalicine as a multi-target directed ligand that have disease modifying potential for amelioration of AD.

Objectives: The brain of mammals contains two major form of cholinesterase enzymes, acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE). The dual inhibition of these enzymes is considered as a promising strategy for the treatment of neurological disorder such as Alzheimer's disease (AD), senile dementia, ataxia, and myasthenia gravis. The present study was undertaken to explore the anticholinesterase inhibition property of allicin. Materials and Methods: An assessment of cholinesterase inhibition was carried out by Ellman's assay. Results: The present study demonstrates allicin, a major ingredient of crushed garlic (Allium sativum L.) inhibited both AChE and BuChE enzymes in a concentration-dependent manner. For allicin, the IC ₅₀ concentration was 0.01 mg/mL (61.62 μM) for AChE and 0.05 ± 0.018 mg/mL (308.12 μM) for BuChE enzymes. Conclusions: Allicin shows a potential to ameliorate the decline of cognitive function and memory loss associated with AD by inhibiting cholinesterase enzymes and upregulate the levels of acetylcholine (ACh) in the brain. It can be used as a new lead to target AChE and BuChE to upregulate the level of ACh which will be useful in alleviating the symptoms associated with AD.

Alzheimer’s disease (AD) is characterized by depositions of amyloid β (Aβ) peptides aggregates resulting in plaques formation in the central nervous system (CNS). This study evaluates the disease-modifying potential of scopoletin against multiple factors associated with AD such as cholinesterase enzymes, Aβ peptides, and neuroprotective properties against Aβ- and H₂O₂-induced cytotoxicity under in vitro conditions. Scopoletin was identified and quantified using UPLC-QTOF (ultra-high performance liquid chromatography-quadrupole time-of-flight) and high-performance liquid chromatography (HPLC), respectively. The antiamyloidogenic potential was evaluated by thioflavin T and congo red binding assay. Inhibition of key enzymes, that is, acetylcholinesterase and butyrylcholinesterase, was investigated by Ellman’s assay. UPLC-QTOF analysis showed that most abundant phytoconstituent present in Argyreia speciosa hydroalcoholic root extract was scopoletin followed by festuclavine and ergometrine. Scopoletin was further quantified using novel reverse phase (RP)-HPLC method developed in this study. The neuroprotective potential of scopoletin was found to be 69% against Aβ42-induced neurotoxicity and 73% against H₂O₂-induced cytotoxicity in PC12 cell culture at 40 μM final concentration. At the same concentration, scopoletin inhibited Aβ42 fibril formation up to 57%. The IC₅₀ concentration for AChE and BuChE enzyme inhibition by scopoletin was 5.34 and 9.11 μM, respectively. The antiaggregation and enzyme inhibition results were complemented with strong molecular interactions of scopoletin with target proteins validated by in silico molecular docking analysis. Based on this study, it can be concluded that scopoletin can be used as a lead for amelioration of symptoms and disease-modifying effects in AD.