Current and novel therapeutic molecules and targets in Alzheimer’s disease (original) (raw)
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The purpose of our study is to identify phosphorylated tau (p-tau) inhibitors. P-tau has recently received great interest as a potential drug target in Alzheimer's disease (AD). The continuous failure of Aβ-targeted therapeutics recommends an alternative drug target to treat AD. There is increasing evidence and growing awareness of tau, which plays a central role in AD pathophysiology, including tangles formation, abnormal activation of phosphatases/kinases, leading p-tau aggregation in AD neurons. In the present study, we performed computational pharmacophore models, molecular docking, and simulation studies for p-tau in order to identify hyperphosphorylated sites. We found multiple serine sites that altered the R1/R2 repeats flanking sequences in the tau protein, affecting the microtubule binding ability of tau. The ligand molecules exhibited the p-O ester scaffolds with inhibitory and/or blocking actions against serine residues of p-tau. Our molecular docking results revealed five ligands that showed high docking scores and optimal protein-ligand interactions of p-tau. These five ligands showed the best pharmacokinetic and physicochemical properties, including good absorption, distribution, metabolism, and excretion (ADME) and admetSAR toxicity tests. The p-tau pharmacophore based drug discovery models provide the comprehensive and rapid drug interventions in AD, and tauopathies are expected to be the prospective future therapeutic approach in AD.
Factors Influencing the Potency of Alzheimer Inhibitors: Computational and Docking Studies
American journal of Alzheimer's disease and other dementias, 2018
Density functional theory (B3LYP/6-31G [d]) is performed to study the effect of molecular and electronic structures of the investigated β-secretase 1 (BACE1) Alzheimer's inhibitors on their biological activities and discuss the correlation between their inhibition efficiencies and quantum chemical descriptors. IC50 values of the investigated compounds are mostly affected by the substituted R2 phenyl moiety. The calculations show that the presence of electron withdrawing group increases the half maximal inhibitory concentration (IC50). Structure-activity relationship studies show that the electronic descriptors, energy of high occupied molecular orbital, ΔE, lipophilicity, hardness, and ionization potential index, are the most significant descriptors for the correlation with IC50. Molecular docking simulation is performed to explain the mode of interaction between the most potent drug and the binding sites of the BACE1 target. A good correlation between the experimental and the t...
Identification of biomolecules for Alzheimer's disease using docking analysis of tau protein
NeuroPharmac Journal
Objective: In-silico methods to find and characterize the ligands against the active site of tau protein which could assist in the therapeutics of Alzheimer's disease. Methods: The aid of various bioinformatic tools such as phylogenetic analysis, homology modeling, and active site prediction led to the molecular docking analysis of the major malefactor for Alzheimer’s disease ‘microtubule- associated tau protein’. A three-dimensional structure of microtubule-related tau protein was created, and the Ramachandran plot was acquired for quality appraisal. Results: Procheck showed 62.95 of residues in the most preferred region with 20% residues in the additional allowed region and 5.7 % in the disallowed region of microtubule-associated tau protein. Screenings of the particles were done dependent on Lipinski's standard of five. Conclusion: Genistein, Hesperidin, and epigallocatechin-3 are the potential ligands in regulating microtubule-related tau protein and Epigallocatechin-3 g...
BioMed Research International, 2014
Alzheimer’s (AD) is the leading cause of dementia among elderly people. Considering the complex heterogeneous etiology of AD, there is an urgent need to develop multitargeted drugs for its suppression.β-amyloid cleavage enzyme (BACE-1) and acetylcholinesterase (AChE), being important for AD progression, have been considered as promising drug targets. In this study, a robust and highly predictive group-based QSAR (GQSAR) model has been developed based on the descriptors calculated for the fragments of 20 1,4-dihydropyridine (DHP) derivatives. A large combinatorial library of DHP analogues was created, the activity of each compound was predicted, and the top compounds were analyzed using refined molecular docking. A detailed interaction analysis was carried out for the top two compounds (EDC and FDC) which showed significant binding affinity for BACE-1 and AChE. This study paves way for consideration of these lead molecules as prospective drugs for the effective dual inhibition of BAC...
Cholinesterase inhibitors (ChE-Is) are the standard of therapy for treatment of patients with Alzheimer’s disease (AD) and are the only class of drugs approved by the Food and Drug Administration (FDA) for treatment of this condition. In this paper we used the new approach utilizing cheminformatics tools such as CORINA, Yet Another Scientific Artificial Reality Application (YASARA), and molecular docking program to identify binding affinity and mechanism of interaction between the ChE-Is with the target proteins. This approach should be helpful to understand the selectivity of the given drug molecule in the treatment of Alzheimer’s disease.
INTERNATIONAL JOURNAL OF PHARMACEUTICAL SCIENCES, 2024
Objective: Alzheimer disease (AD) is a progressive neurodegenerative condition. Acetylcholine (Ach), a neurotransmitter that is essential for many cognitive and neuropsychiatric function, is significantly reduced is AD patient's brains. Method: In the present insilico study, 43 bioactive compounds of Eburnane type of Natural bioactive alkaloids were analyzed for their inhibitory role on Acetylcholinesterase (AChE) activity by applying the molecular docking studies. Other parameters viz. protein-ligand interactions, determination of molecular interactionbased binding affinity values, Lipinski rule of five, functional properties and biological activities for the above compounds were also calculated by employing the appropriate bioinformatics tools. Result: The results of docking analysis clearly showed that 13 chemical molecules model Out of 43 model shows the more binding affinity but molecule 4ey7_A11 has highest binding affinity with AChE (-11.9 kcal/mole) has least percentage activity on AD and neurodegenerative disease. Whereas, the 4ey7_A35 has been second qualified binding affinity (-10.9 kcal/mol). Conclusion: We have determined that 4ey7_A11 is the best molecular fit to investigate further for the treatment of AD based on docking results.
Molecular drug targets and therapies for Alzheimer’s disease
Translational Neuroscience, 2014
Alzheimer’s disease (AD) is a neurodegenerative disorder that is characterized by normal memory loss and cognitive impairment in humans. Many drug targets and disease-modulating therapies are available for treatment of AD, but none of these are effective enough in reducing problems associated with recognition and memory. Potential drug targets so far reported for AD are β-secretase, Γ-secretase, amyloid beta (Aβ) and Aβ fibrils, glycogen synthase kinase-3 (GSK-3), acyl-coenzyme A: cholesterol acyl-transferase (ACAT) and acetylcholinesterase (AChE). Herbal remedies (antioxidants) and natural metal-chelators have shown a very significant role in reducing the risk of AD, as well as lowering the effect of Aβ in AD patients. Researchers are working in the direction of antisense and stem cell-based therapies for a cure for AD, which mainly depends on the clearance of misfolded protein deposits — including Aβ, tau, and alpha-synuclein. Computational approaches for inhibitor designing, inte...
Determination of Potential Multi-Target Inhibitors of Alzheimer’s Disease in Silico
2019
The complexity of Alzheimer’s disease requires therapeutic treatments that counteract multiple processes. Symptoms and causes include formation of senile plaques, agglomeration of neurofibrillary tangles, disruption of cholinergic activity, and oxidative stress. Enzymes that promote these pathways include BACE1, GSK-3β, CDK-5, AChE, BuChE, MAO-A, and MAO-B. Virtual screening of the InterBioScreen and Zinc 15 databases was conducted using the Schrödinger 2019 Phase program to identify potential inhibitors of these enzymes. InterBioScreen compounds 1N-05528, and 1N-72595, and Zinc 15 compounds ZINC314161, ZINC5854353, ZINC15674654, ZINC49170543, ZINC96112244, and ZINC604382088 all showed exergonic binding within the active sites of at least five AD enzymes. These compounds were docked individually with standard precision (SP) and compared with known inhibitors—the docking locations and scores were comparable with those of known inhibitors. ADME blood brain permeability evaluations wit...