C. Remya

Design of potent inhibitors of acetylcholinesterase using morin as the starting compound

Inhibition of acetylcholinesterase (AChE) is a promising treatment strategy for Alzheimers disease (AD). Oxidative stress, inflammation and accumulation of metal ions at sites of neurodegeneration have been observed in association with AD. Flavonoids are well known for their action against inflammation and oxidative stress. Hence, they can be used for treating diseases such as AD, cancer, atherosclerosis and Parkinsons disease. Flavonols such as quercetin, myricetin, galangin, fisetin and kaempferol have been reported as inhibitors of AChE. In the present work, the enzyme inhibitory properties of morin, a flavonol, has been tested against AChE. The binding pattern of morin and 12 other flavonols at the active site of human AChE has been analyzed using molecular modeling and docking methods. In order to enhance the binding affinity of AChE for morin, in silico structural modification of the compound was carried out. The structural elements responsible for its biological functions were retained during the modification. Some of the derivatives possessed better binding energies than morin and hence they could be used as drug lead compound for the treatment of AD.

Flavanone glycosides as acetylcholinesterase inhibitors: computational and experimental evidence.

Acetylcholinesterase hydrolyzes the neurotransmitter called acetylcholine and is crucially involved in the regulation of neurotransmission. One of the observable facts in the neurodegenerative disorders like Alzheimers disease is the decrease in the level of acetylcholine. Available drugs that are used for the treatment of Alzheimers disease are primarily acetylcholinesterase inhibitors with multiple activities. They maintain the level of acetylcholine in the brain by inhibiting the acetylcholinesterase function. Hence acetylcholinesterase inhibitors can be used as lead compounds for the development of drugs against AD. In the present study, the binding potential of four flavanone glycosides such as naringin, hesperidin, poncirin and sakuranin against acetylcholinesterase was analysed by using the method of molecular modeling and docking. The activity of the top scored compound, naringin was further investigated by enzyme inhibition studies and its inhibitory concentration (IC50) towards acetylcholinesterase was also determined.

Interactions of selected indole derivatives with phospholipase A2: in silico and in vitro analysis

AbstractPhospholipase A2 (PLA2) is one of the key enzymes involved in the formation of inflammatory mediators. Inhibition of PLA2 is considered to be one of the efficient methods to control inflammation. In silico docking studies of 160 selected indole derivatives performed against porcine pancreatic PLA2 (ppsPLA2) suggested that, CID2324681, CID8617 (indolebutyric acid or IBA), CID22097771 and CID802 (indoleacetic acid or IAA) exhibited highest binding energies. In silico analysis was carried out to predict some of the ADME properties. The binding potential of these compounds with human non pancreatic secretory PLA2 (hnpsPLA2) was determined using molecular docking studies. In order to corroborate the in silico results, enzyme kinetics and isothermal titration calorimetric analysis of the two selected compounds, IAA and IBA were performed against ppsPLA2. From the analysis, it was concluded that IAA and IBA can act as competitive inhibitors to the enzyme and may be used as anti inflammatory agents. FigureInhibitory activity of IAA and IBA against PLA2

Functionalised dihydroazo pyrimidine derivatives from Morita–Baylis–Hillman acetates: synthesis and studies against acetylcholinesterase as its inhibitors

A wide array of dihydro[1,5]azo[1,2-a]pyrimidine 2-esters have been synthesised at room temperature in moderate to good yields through one-pot reaction between nitrostyrene derived MBH acetates and aminoazole derivatives with γ-α cyclisation. The reaction involves a cascade SN2 reaction followed by intramolecular Michael addition–cyclisation with the generation of two new carbon–nitrogen bonds. The structure was further confirmed by single X-ray crystal analysis. Docking and in vitro studies of dihydrobenzimidazo pyrimidine derivatives against acetylcholinesterase (AChE) have been performed and the compounds 3d and 3e exhibit potent inhibitory activities with an IC50 of 46.8 nM and 42.5 nM respectively.

An in silico approach for the identification of inhibitors against Acetylcholinesterase

Acetylcholinesterase (AChE) is one of the crucial enzymes involved in nerve response and function. The loss of cholinergic activity is mainly characterized by the rapid hydrolysis of acetylcholine by AChE, which leads to a neurodegenerative disorder called Alzheimer’s disease (AD). Donepezil, an efficient inhibitor of AChE, is widely used in the therapy of AD. The compounds which show above 50% similarity to donepezil were collected from ZINC database. Virtual screening and Induced Fit Docking analysis of these compounds against AChE were carried out to explore the compounds with better binding affinity than donepezil. ADME profile was carried out to identify the compounds having potential to be a drug. The biological activity spectrum of compounds was determined using a program called PASS. Binding potential of the selected compounds toward BChE was also analyzed. In silico analysis proved that compounds such as ZINC13802320, ZINC11709541, ZINC08750211, ZINC02040474, and ZINC49718337 can be used as a lead compounds for the development drugs against AD.

Inhibitory activity of IAA and IBA against lipoxygenase: in silico and in vitro validation

Inhibition of leukotriene biosynthesis is considered to be one of the potential treatment strategies for controlling inflammation, respiratory diseases and many neurodegenerative disorders. Designing of specific functional inhibitors against Lipoxygenases (LOX) has got considerable attention due to its ability to block leukotriene biosynthesis. Molecular docking analysis of two indole derivatives such as indoleacetic acid (IAA) and indolebutyric acid (IBA) are reported here. Both compounds give glide scores better than that of protocatechuic acid and nitro catechol, the two known LOX inhibitors. From the enzyme kinetic analysis, it was revealed that IAA and IBA inhibit competitively. The IC50 values determined for both IAA and IBA were 42.98 μM and 17.82 μM, respectively. The binding free energy of these compounds was determined using isothermal titration calorimetric assay and was found to be − 6.12 kcal/mol for IAA and − 7.84 kcal/mol for IBA. From the analysis, it can be concluded that both IAA and IBA might be useful as anti-inflammatory agents.

An in silico guided identification of nAChR agonists from Withania somnifera

ABSTRACT In Indian traditional practice of medicines, numerous plants have been used against various neurodegenerative disorders like Alzheimers disease (AD). Withania somnifera (Ashwagandha in Sanskrit) is one of the medicinal plants exhibiting broad spectrum activity against various diseases. Due to its ability to improve cognitive functions, aswagandha extracts are used in various memory supplements. In the present study, the pharmacological activity of various bioactive compounds of aswagandha has been studied with respect to AD. The blood brain barrier penetrability and central nervous system (CNS) activity of these bioactive compounds were predicted using in silico tools. The predicted pharmacological properties and structure activity relationship focuses that the compounds such as anaferine, anahygrine, cuscohygrine and isopelletierine can be CNS active and neuronal nicotinic acetylcholine receptor (nAChR) agonists. In order to investigate the structure activity relationship results, molecular modeling studies has been carried out with promising ligands against nAChR. It is a known fact that the agonists of nAChRs are capable to improve communication between neurons and hence these compounds may be useful as lead compounds for the development of drugs against neurodegenerative disorders. This study also indirectly focuses how ayurvedic formulations (those containing aswagandha) are effective against neurodegenerative disorders.

Binding of NDGA and morin with phospholipase A2: experimental and computational evidences

The effects of morin and nordihydroguaiaretic acid (NDGA), two plant secondary metabolites, on porcine pancreatic phospholipase A2 (PLA2) were investigated by isothermal titration calorimetry (ITC) and in silico docking analyses. The binding energies obtained for NDGA and morin from the ITC studies are − 6.36 and − 5.91 kcal mol− 1, respectively. Similarly, the glide scores obtained for NDGA and morin towards PLA2 were − 7.32 and − 7.23 kcal mol− 1, respectively. Further the docked complexes were subjected to MD simulation in the presence of explicit water molecules to check the binding stability of the ligands in the active site of PLA2. The bound ligands make hydrogen bonds with the active site residues of the enzyme and coordinate bonds with catalytically important Ca2+ ion. The binding of ligands at the active site of PLA2 may also contribute to the reported anti-inflammatory properties of NDGA and morin.

Inhibition, ADME and structure based modification of IAA and IBA against acetylcholinesterase: an attempt towards new drug development for Alzheimer's disease

Indole derived compounds have gained considerable attention in the pharmaceutical industry due to their pharmacological and structural properties. Indole-3-acetic acid (IAA) and indole 3-butyric acid (IBA) are two indole derivatives used in plant tissue culture experiments. They are plant growth regulators generally known as auxins. Since acetylcholinesterase (AChE) inhibitors prevent the hydrolysis of neurotransmitter acetylcholine, they may be suitable for the treatment of Alzheimers disease. The IC50 and atomic level interaction of IAA and IBA against AChE were determined by enzyme inhibition and molecular docking studies. In order to improve central nervous system activity and blood brain permeability, in silico modification of the structure has been carried out. The modified compounds were screened by docking against AChE and butyrylcholinesterase (BChE). Based on the docking studies, four new derivatives have been identified for drug development against neurodegenerative disorders such as Alzheimers disease.

Designing of multi-target-directed ligands against the enzymes associated with neuroinflammation: an in silico approach

Due to the role that neuroinflammation (NI) has in neurodegenerative disorders, reducing NI is an effective way to control their progression. In the present study, 67 hybrids were designed by combining indole derivatives with selected non-steroidal anti-inflammatory drugs (NSAIDs); of these 13 hybrids were selected on the basis of their absorption, distribution, metabolism, and excretion (ADME) and physicochemical properties. The compounds were docked to the active site of enzymes PLA2, LOX-5 and COX-2 and binding energies were calculated using the Molecular Mechanics - Generalized Born Surface Area (MM-GBSA) method. The hybrids were clustered into three groups based on their binding free energies using the k-means clustering method. Three hybrids with better binding energies towards all the targets were selected and compared with those of some known inhibitors of their respective targets. The studies suggest that the proposed hybrids may be promising in controlling NI. Since NI is well connected with AD, the modes of binding of these hybrids with cholinesterase enzymes were also studied.