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. 2013 Jun 20;4(4):186–200.

Functional Analysis and Molecular Docking studies of Medicinal Compounds for AChE and BChE in Alzheimer’s Disease and Type 2 Diabetes Mellitus

Dowluru SVGK Kaladhar 1,*, Nagendra Sastry Yarla 1, N Anusha 1
PMCID: PMC3733582  PMID: 23936743

Abstract

Acetylcholinesterase and Butyrylcholinesterase share unravelling link with components of metabolic syndromes that’s characterised by low levels of HDL cholesterol, obesity, high fast aldohexose levels, hyper-trigliceridaemia and high blood pressure, by regulation of cholinergic transmission and therefore the enzyme activity within a living system. The phosphomotifs associated with amino acid and tyrosine binding motifs in AChE and BChE were known to be common. Phylogenetic tree was constructed to these proteins usinf UPGMA and Maximum Likelihood methods in MEGA software has shown interaction of AChE and BChE with ageing diseases like Alzheimer’s disease and Diabetes. AChE has shown closely related to BChE, retinol dehydrogenase and β-polypeptide. The present studies is also accomplished that AChE, BChE, COLQ, HAND1, APP, NLGN2 and NGF proteins has interactions with diseases such as Alzheimer’s and D2M using Pathwaylinker and STRING. Medicinal compounds like Ortho-7, Dibucaine and HI-6 are predicted as good targets for modeled AChE and BChE proteins based on docking studies. Hence perceptive studies of cholinesterase structure and the biological mechanisms of inhibition are necessary for effective drug development.

Keywords: AChE, BChE, Protein interactions, Phylogeny, Docking

Acetylcholinesterase (acetylhydrolase or AChE) could be a serine protease that hydrolyzes acetylcholine that acts because the neurochemical in varied species [1, 2]. AChE (Acetylcholinesterase) and BChE (Butyrylcholinesterase) belongs to carboxylesterase family of enzymes. AChE is principally found in several varieties of conducting tissue that serves to terminate junction transmission [3, 4, 5]. Biogenic amines will intervene many varieties of living thing communication in cellular organisms and somewhat evidence has indicated that biogenic amines produce intracellular responses aside from by triggering the protein production of second messengers [6].

AChE and BChE involve in control cholinergic transmission and also the proteinase activity and develops Alzheimer’s as a result of production of the β-amyloid macromolecule [7]. AChE catalysis the hydrolysis of acetylcholine of neurotransmitter to acetate and choline at cholinergic nerve terminals and terminates the action of AChE on postsynaptic receptors. BChE involves interactions inside the system in three different enzymatic activities in its structures like AChE, aryl acylamindase and proteinase [8].

Neuronic complications taking place in D2M (Diabetes Mellitus Type 2) is influenced as a result of AChE activity by membrane surface development characterised by morphological changes related to minimized motor and sensory conductivity velocities and is being corrected by hypoglycemic agent treatment [9]. The insertion of membrane proteins into the membrane core is also passionate about transmembrane potential that will have an effect on lipid-protein interaction [10] and these activities emerge in association with plaques and tangles in AD (Alzheimer’s disease). This pathological cholinesterase with altered properties of AChE and BChE turn out additional severe cases in increasing variety of plant tissue and neurocortical amyloid made cerebral cortex amyloid made neurotic plaques and neurofibrillary tangles in manifestations of AD [11].

AChE is found exuberant in brain, muscle, and blood corpuscle membrane, whereas BChE has higher activity in liver, intestine, heart, excretory organ and respiratory organ. AChE and BChE contribute 65 percent aminoalkanoic acid sequence similarity and have connected molecular forms despite of being merchandise of various genes lying on human chromosomes 7(7q22) and 3(3q26) [12]. The active site within the structure of human BChE gap is schematized and therefore the peripheral ionic site (PAS) is found at the mouth of the gorge. Asp70 and Tyr332 residues of PAS are initial binding of charged substrates and have a bond that controls the operate design of the BChE situation gorge [13]. BChE could be a major detoxification protein of cocain in plasma with inactive metabolites made, like ecgonine methyl ester and benzoic acid, are rapidly excreted by kidney. A signal of cocain toxicity includes elevated vital sign, pathology grand-mal seizure and stroke. BChE protects from deadly effects of cocain by management of purified human serum [14]. AD and D2M occur with increasing frequency as age advances and disease development results in risk of onset of another disease.

In the risk of AD and D2M, a range of mechanisms has been postulated like metabolic abnormalities of insulin resistance, dyslipidemia, high blood pressure, hypertension, hyperglycaemia, disturbing synaptic plasticity learning and memory [15]. BChE is related to interstitial tissue cells, epithelial tissue cells and neurons BChE which will be known from AChE in its kinetic response to concentration of acetylcholine. BChE hydrolysis high concentration of acetylcholine and is related to interstitial tissue cells [16]. In cell cultures and epidemiologic surveys, agents such as herbal extracts with inhibitor property and NSAID (nonsteroidal anti-inflammatory drugs) showed protecting impact against AD pathology [17, 18, 19].

Exposure to organophosphate pesticides disrupts neurotransmission by inhibiting conjugation AChE resulting in acetylcholine accumulation within the junction and neural over stimulation result in death due to cardiovascular and respiratory collapse [20]. Inhibition of AChE and BChE by organophosphorus compounds take in a very progressive manner and also the reactivation of phosphorylated accelerator are often done by treating with sturdy nucleophilic agents like oximes [21]. More than 10,000 molecules of acetylcholine are often cleaved per second in brain by AChE and BChE. AChE knockout mouse survives for many weeks in absence of AChE as a result of AChE is remunerated by BChE and provides backup and regulates cholinergic transmission that shows the precise cholinergic pathways regulated by BChE in brain of patients with AD [22].

Most of the proteins within the cell move with alternative protein molecules so a lot of essential for cellular method like cellular motion, signal transduction, transportation and most restrictive mechanism that are mediate by protein-protein interaction [23]. These proteins will have measurable effects in altering the kinetic properties of the cellular components. These transient altering are consequence of protein kinases, protein phosphotases, acyltransferases, glycosyl transferases, etc [24]. Experimental knowledge on physical protein-protein interactions are largely hold on and a STRING (Search Tool for Retrieval of INteracting Gene) info provides data on useful links between proteins [25]. Signalink info may be a uniformly curetted info of eight major signalling pathways [26]. HPRD (Human Protein Reference Database) is internet primarily based community[27, 28], a unique comprehensive protein data resource that depicts completely different options of proteins like domain structure, post-translational modifications, tissue expression, protein-protein interactions, enzyme-substrate relationships and molecular function.

Protein-Protein interactions play a crucial role in identification of metabolic syndrome pathways, provides advancements from the past for understanding molecular options for vital network topologies in biological systems [29]. AChE and BChE are often found in blood and is related to options of the metabolic syndrome [30]. Central and involuntary nervous systems regulate immediate variations with AChE and BChE activity that’s crucial with chemical change properties and general functions. Factor and haplotype variations within the enzyme genes were related to changes in blood. Both AChE and BChE activities brings changes in plasma lipid and lipoprotein concentrations, obesity and additional elements of the metabolic syndrome.

The MetS (metabolic syndrome) is characterised by abdominal obesity, low levels of high-density lipoprotein (HDL) sterol, elevated fast aldohexose levels and hyper-trigliceridaemia with cardiovascular disease [31, 32] during involvement of AChE and BChE in lipid metabolism. BChE, AChE and Neuroligin structurally belong to a family of alpha beta hydrolase fold and are inferred from the similar structural patterns [33]. Diabetes, Obesity and Neurological disturbances show co-occurrence by activity a comparative analysis with NLGN2 (Neuroligin) a protein belonging to the same family, alters the signal transduction of neurons, a possible reason for Neurological disturbances.

The brain of mammals contains two major forms of cholinesterases, AChE and BChE have similar perform to enzymatic differences however show variations genetically, structurally and for and for their kinetics [34]. AChE activity decreases progressively whereas BChE activity shows some increase within the brain of AD patients.

Cholinesterase inhibitors (ChEIs) are efficacious for mild to moderate AD exert 3 main actions: inhibit enzyme (ChE), increase extracellular levels of brain neurotransmitter (ACh) and improve psychological feature processes [35]. Severely and selectively damaged central cholinergic systems are concerned neurodegenerative diseases like Alzheimer’s disease and dementia with Lewy bodies [36, 37].

MATERIALS AND METHODS

AChE and BChE are interlinked with various proteins related to AD and D2M. To find out the protein interactions, an interaction profile studies and experimental graphs has been studied using STRING database.

Sequence retrieval

The National Centre for Biotechnology Information advances science and health by providing data access to biomedical and genomic information. The NCBI stores genome sequencing data in GenBank and an index of biomedical research analysis articles in PubMed and PubMed Central, in addition as alternative information relevant to biotechnology. All these databases are accessible on-line through the Entrez search engine.

The interaction profile data from HPRD has presented good signaling profile and hence protein sequences related to these proteins has been retrieved for further studies.

The molecular weight of AChE is 67376 Da present in gene map locus at 7q22. AChE interacts with various molecules such as Proline rich membrane anchor 1, Collagen-like tail subunit (single strand of homotrimer) of asymmetric acetylcholinesterase, HAND1, Ligatin, Laminin, alpha 1, Laminin beta 1, Collagen, type IV, alpha 1, Amyloid beta A4 protein. The sequence of AChE retrieved for modelling of receptor is:

>AChE sequence MRPPQCLLHT PSLASPLLLL
LLWLLGGGVG AEGREDAELL VTVRGGRLRG
IRLKTPGGPV SAFLGIPFAE PPMGPRRFLP
PEPKQPWSGV VDATTFQSVC YQYVDTLYPG
FEGTEMWNPN RELSEDCLYL NVWTPYPRPT
SPTPVLVWIY GGGFYSGASS LDVYDGRFLV
QAERTVLVSM NYRVGAFGFL ALPGSREAPG
NVGLLDQRLA LQWVQENVAA FGGDPTSVTL
FGESAGAASV GMHLLSPPSR GLFHRAVLQS
GAPNGPWATV GMGEARRRAT QLAHLVGCPP
GGTGGNDTEL VACLRTRPAQ VLVNHEWHVL
PQESVFRFSF VPVVDGDFLS DTPEALINAG
DFHGLQVLVG VVKDEGSYFL
VYGAPGFSKD NESLISRAEF LAGVRVGVPQ
VSDLAAEAVV LHYTDWLHPE DPARLREALS
DVVGDHNVVC PVAQLAGRLA AQGARVYAYV
FEHRASTLSW PLWMGVPHGY EIEFIFGIPL
DPSRNYTAEE KIFAQRLMRY WANFARTGDP
NEPRDPKAPQ WPPYTAGAQQ YVSLDLRPLE
VRRGLRAQAC AFWNRFLPKL LSATASEAPS
TCPGFTHGEA APRP GLPLPL LLLHQLLLLF
LSHLRRL
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The molecular weight of BChE is 68418 Da and present at gene map locus of 3q26.1-q26.2. It expresses in Brain, plasma and Fetus. It interacts with proteins such as Collagen-like tail subunit (single strand of homotrimer) of asymmetric acetylcholinesterase. The sequence of BChE retrieved for modelling of receptor is:

>BChE sequence
MHSKVTIICI RFLFWFLLLC MLIGKSHTED
DIIIATKNGK VRGM NLTVFG GTVTAFLGIP
YAQPPLGRLR FKKPQSLTKW SDIWNATKYA
NSCCQNIDQS FPGFHGSEMW NPNTDLSEDC
LYLNVWIPAP KPKNATVLIW IYGGGFQTGT
SSLHVYDGKF LARVERVIVV SMNYRVGALG
FLALPGNPEA PGNMGLFDQQ LALQWVQKNI
AAFGGNPKSV TLFGESAGAA SVSLHLLSPG
SHSLFTRAIL QSGSFNAPWA VTSLYEARNR
TLNLAKLTGC SRENETEIIK CLRNKDPQEI
LLNEAFVVPY GTPLSVNFGP TVDGDFLTDM
PDILLELGQF KKTQILVGVN KDEGTAFLVY
GAPGFSKDNN SIITRKEFQE GLKIFFPGVS
EFGKESILFH YTDWVDDQRP ENYREALGDV
VGDYNFICPA LEFTKKFSEW GNNAFFYYFE
HRSSKLPWPE WMGVMHGYEI EFVFGLPLER
RDNYTKAEEI LSRSIVKRWA NFAKYGNPNE
TQNNSTSWPV FKSTEQKYLT LNTESTRIMT
KLRAQQCRFW TSFFPKVLEM TGNIDEAEWE
WKAGFHRWNN YMMDWKNQFN DYTSKKESCV
GL
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MEGA

MEGA (Molecular Evolutionary Genetic Analysis) is an integrated tool used for conducting automatic and manual sequence alignment, inferring phylogenetic trees, mining web-based databases, estimating rates of molecular evolution, inferring ancestral sequences, and testing evolutionary hypotheses.

ClustalW

ClustalW is a widely used system for aligning any number of homologous nucleotide or protein sequences. ClustalW uses progressive alignment techniques for multi-sequence alignments that are useful to construct phylogenetic tree.

Construction of phylogenetic tree

Phylogenetic relationships of genes and the organisms usually are presented in a tree like form in cladistics. The sequences have shown homology with the sequences present in GenBank. The sequences of AChE (AAH94752), retinal dehydrogenase (AAC09250), β-polypeptide (AA126151), BChE (AAH08396) and tau-protein (AAA57264) has been retrieved from GenBank and constructed phylogeny in MEGA software using Maximum Likelihood and UPGMA Methods.

Signalink

PathwayLinker identifies and visualizes the first neighbour interactor network of the queried proteins, analyzes the signaling pathway of the proteins in subnet, and provides links to online web resources. Some of the biomedical research often focuses on altering the functions of selected proteins. PathwayLinker can assist experimental work by linking the queried proteins to signaling pathways through protein-protein and/or genetic interactions.

Human Protein Reference Database (HPRD)

The HPRD is a centralized tool that integrates data bearing on domain design, post-translational modifications, interaction networks and association for every macromolecule within the human protein.

STRING (Search Tool for the retrieval of interacting Genes/Proteins)

STRING is a well known database for predicting protein interactions and embrace physical (direct) and purposeful (indirect) associations between proteins. STRING integrates interaction knowledge from the sources for an outsized range of organisms and transfers information between these organisms wherever applicable.

Molecular modelling and Ligand design

The sequences of AChE and BChE are retrieved from HPRD and modelled for evaluation of docking parameters with the ligands. The sequences have been submitted to Swiss-model and the protein molecules have been saved as .pdb format. Medicinal compounds like Huperzine, Rivastigmine, Ambenonium, Ortho-7, Donepezil, Pyridostigmine, Galanthamine, AChE inhibitor substrate, HI-6 have been selected from literature to test the activity against modelled AChE molecule. Medicinal compounds like Chlorpyrifosoxon, 1-anilino-8-naphthalene sulfonic acid, Dibucaine, Procainamide, Benzoylcholine, Propionyl thicholine, Acetyl thiocholine, Dialkylphenylphosphates, Tetra ethyl ammonium are selected to test the activity against modelled BChE molecule. These 2D ligands have been constructed using ChemSketch, optimised and saved as .mol format. The 2D ligands in .mol format has been opened in Hyperchem, and the 3D structures has been saved as .pdb format.

Docking

Docking is the process of bringing one molecule in vicinity with an another molecule. The present research work is conducted the drug molecules to be docked with the modelled receptors such as AChE and BChE. Docking is conducted using free software’s such as iGemdock v2.0 and Hex v6.0, and a commercial software such as Autodock v4.2.

iGemdock v2.0

iGEMDOCK (iGeneric Evolutionary Method DOCKing) for molecular docking is a program for computing a ligand conformation and orientation relative to the active site of target protein. GEMDOCK has pharmacophore-based scoring function and the results performed based on the homology model.

Autodock v4.2

AutoDock is a suite of automated and commercial docking tool designed to predict small molecules docking to a receptor (diseased or useful components of cell).

Hex v6.0

Hex is an interactive protein docking and molecular superposition program. The instructions from Hex is understands as protein or DNA structures in PDB format. It can also read small-molecule as SDF files.

RESULTS

Sequencing studies of genome and proteome have provides an incredible landmark within the history of biology. A significant role for sequences of DNA is to encode the sequences of proteins that that are participating in essentially all processes. Proteins are flexible, vibrant and extremely complex molecules molecules in a very constant state of modification through initiating and driving interactions with several molecules leads to different cellular states.

Phylogenetic tree was constructed to the proteins showing interaction with AChE and BChE involved in ageing diseases in MEGA. Phylogenetic tree is constructed using UGPMA from MEGA software (UPGMA Method) and relatedness of the proteins was shown in Figure 1.

Figure 1:

Figure 1:

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Clade of AChE and BChE with Alzheimers and D2M (UPGMA Method)

The most challenging part of the phylogeny construction involves comparing the nearest relatives with specific domain content. Phylogenetic tree was constructed to the proteins showing interaction with AChE and BChE involved in agening diseases with Maximum Likelihood method in MEGA (Figure 2). The results predicted that AChE is closely related to retinol dehydrogenase and β-polypeptide. AChE is also shown close relationship with BChE and tau-protein.

Figure 2:

Figure 2:

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Phylogentic Tree Construction using MEGA (Maximum Likelihood Method)

The interaction between AChE and BChE with other proteins like COLQ, APP etc was retrieved from Pathway linker database by submitting the query in search box and the result is represented in Figure 3.

Figure 3:

Figure 3:

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Pathway Linker Results for AChE and BChE

HPRD for AChE and BChE Protein interaction

In HPRD, the information about the protein-protein interaction, post-translational modifications, enzyme-substrate relationships and disease association are retrieved and represented in Figure 4.

Figure 4:

Figure 4:

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Interaction report of Acetylcholinesterase

The query protein related to AChE has been uploaded to HPRD Phosphomotif finder and results were retrieved and protein contains 152 Serine kinase / phosphatase motifs. The results are predicted that PhosphoMotif’s of AChE is related to GSK-3, ERK1, ERK2, CDK5 substrate motif, G protein-coupled receptor kinase 1 substrate motif, X DNA dependent Protein kinase substrate motif, Casein Kinase I and II substrate motifs GSK-3, ERK1, ERK2, CDK5 substrate motif, PKA kinase substrate motif, PKC kinase substrate motif, Calmodulindependent protein kinase II substrate motif, Growth associated histone HI kinase substrate motif, PP2C delta substrate motif, b-Adrenergic Receptor kinase substrate motif, Dual specificity protein phosphatase 6 substrate motif, MAPK 11, 13, 14 Kinase substrate motif, Pyruvate dehydrogenase kinase substrate motif, Pim1 kinase substrate sequence, LKB1 Kinase substrate motif, NIMA kinase substrate motif, AMP-activated protein kinase substrate motif, Chk1 kinase substrate motif.

In the query protein AChE there are 16 Serine binding motifs as WW domain binding motif, 14-3-3 domain binding motif, MDC1 BRCT domain binding motif and Plk1 PBD domain binding motif. For the given query BChE information about protein-protein interaction, disease association, post-translation modification, enzyme substrate relationships are retrieved using HPRD (Figure 5).

Figure 5:

Figure 5:

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Interaction report of Butyrylcholinesterase

The number of serine kinase / phosphatase in the protein BChE is retrieved. There are 157 Serine kinase / phosphatase motifs such as AMP-activated protein kinase substrate motif, Casein Kinase I and II substrate motif, PKA kinase substrate motif, PKC kinase substrate motif, Chk1 kinase substrate motif, Calmodulin-dependent protein kinase II substrate motif, G protein-coupled receptor kinase 1 substrate motif, PP2C delta substrate motif, Dual specificity protein phosphatase 6 substrate motif, b-Adrenergic Receptor kinase substrate motif, G protein-coupled receptor kinase 1 substrate motif, GSK-3, ERK1, ERK2, CDK5 substrate motif and CLK1 kinase substrate motif.

The query protein BChE was submitted in the phosphomotifs finder and the number of serine binding motifs was retrieved and there are 12 Serine binding motifs such as MDC1 BRCT domain binding motif, Plk1 PBD domain binding motif and WW domain binding motif.

The proteins AChE and BChE were given in STRING database and its interaction with various proteins were retrieved where it shows interaction with some of the proteins like NGF, COLQ and HSPQ2 (Figure 6 and 7).

Figure 6:

Figure 6:

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AChE and BChE Interactions shown in STRING Database

Figure 7:

Figure 7:

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Protein Interactions with genes responsible to metabolic syndrome

The proteins AChE and BChE were given in STRING database and its interaction with various proteins were retrieved, where it shows direct interactions with some of the proteins like NGF (linked to Alzheimer’s disease), COLQ (associated with Congenital myasthenic syndromes (CMS)), NGF (cause of Alzheimers disease and atherosclerotic cardiovascular disease), NLGN2 ( associated with Alzheimers disease and autism), etc (Figure 8).

Figure 8:

Figure 8:

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AChE and BChE interaction mapping

Docking is a mechanism used to increase enzyme–substrate specificity and govern the binding of kinases and phosphatases to each other and other effectors that provides an understanding of protein–protein interaction permitting fundamental insight to the researchers. Docking surfaces encode specific information about kinase or phosphatase interactions in the framework of many related peptide motifs. Docking results with some ligands has been presented in Figure 9.

Figure 9:

Figure 9:

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Docking results

Homology modelled structure of BChE docking was performed with ligands using AutoDock and ligand Benzoylcholine with energy of −5.31 kcal/mol showed good binding affinity compared with other ligands (Table 2).

Table 2.

Docking Results for Modelled BChE with ligands (AutoDock)

Properties Chlorpyrifosoxon 1-anilino-8-naphthalene sulfonic acid Dibucaine Procainamide Benzoylcholine Propionylthicholine Acetyl Thio choline Dialkylphenyl Phosphates Tetra ethyl ammonium
Binding-energy 0.27 −0.49 0.51 0.58 −5.31 0.23 −4.23 1.09 0.82
Ligand-efficiency 0.02 −0.02 0.02 0.03 −0.35 0.02 −0.42 0.08 0.09
Inhib-constant - 437.51 - - 127.78 - 794.59 - -
Inhib-constant–units - Mm - - Um - Um - -
Intermol-energy −0.32 0.49 0.21 0.28 −5.31 0.23 −4.23 −0.41 0.22
Vdw-hb-disolve-energy −0.32 −0.47 0.29 −0.25 −4.52 0.26 3.59 −0.4 −0.31
Electrostatic-energy −0.01 −0.02 0.5 0.53 −0.8 0.49 −0.64 0.0 0.53
Total-energy 0.23 0.0 0.07 −0.06 0.0 0.0 0.0 −0.49 0.11
Torsional-energy 0.6 0.0 0.3 0.3 0.0 0.0 0.0 1.49 0.6
Unbound-energy −0.23 0.0 0.07 −0.06 0.0 0.0 0.0 −0.49 −0.11
ClRMS 0.0 0.7 0.0 0.0 0.0 0.0 0.0 0.0 0.0
RefRMS 86.69 87.98 94.47 92.5 102.11 97.06 104.0 98.24 86.94
Rseed1 None None None None None None None None None
Rseed2 None None None None None None None None None
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Modelled AChE was docked with its ligands in iGemDock and the energy values, VDW, HBond and Electrostatic information was retrieved. Ortho-7 with energy −83.99 kcal mol−1 has shown good docking results (Table 3).

Table 3.

Binding energies of Modelled AChE and Ligands in kcal mol−1 using iGEMDOCK

Compound Energy VDW HBond Elec
Rivastigmine −65.5849 −58.2418 −7.34309 0
ACHE inhibitor substrate −49.5339 −49.5339 0 0
Ambenoniun −73.3879 −67.907 −5.48089 0
Donepezil −82.7563 −82.7563 0 0
Galanthamine −78.1548 −78.1548 0 0
HI-6 −76.1653 −64.3835 −11.7818 0
Huperzine −62.5742 −59.1771 −3.39709 0
Ortho-7 −83.9951 −77.0341 −6.96104 0
Pyridostigmine-1 −60.7988 −57.2988 −3.5 0
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iGemDock is a tool used for docking using this tool, modelled BChE protein was docked with its ligands and results were retrieved which are shown in the Table 4 and the interaction of Dibucaine is shown in the Figure 9. Dibucaine showed better docking results with BChE with binding energy value of −65.3 kcal mol−1 compared with other tested compounds.

Table 4.

Modelled BChE and its Ligands Docking Results in kcal mol−1 (using iGemDock)

Compound Energy VDW HBond Elec
Acetylthiocholine −35.022 −34.3761 0 −0.645895
1-anilino-8-naphthalenesulfonicacid −59.871 −43.1287 −16.7423 0
Benzoylcholine −49.1163 −44.3803 −4.14502 −0.591029
Chlorpyrifos −54.4679 −40.8784 −13.5895 0
Dialkylphenylphosphates −50.2987 −35.1747 −15.124 0
Dibucaine −65.3374 −58.3615 −6.97593 0
Procainamide −48.351 −42.5862 −5.76476 0
Tetraethylammonium −28.2795 −28.2795 0 0
Propionylthiocholine −41.4 −31.13 −10.3 0.03
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Docking was performed for modelled AChE with nine ligands using Hex. Ortho-7 showed better docking results with binding energy value of −3764 kcal/mol and distance with 4 Angstroms (Table 5).

Table 5.

Docking Result for Modelled AChE and its Ligand in kcal mol−1 (using Hex)

LIGAND Etotal in kcal mol(-1) R-Value In °A
Donepezil −235.98 17.6
Galanthamine −235.98 17.6
HI-6 −229.82 19.2
Rivastigmine −185.69 12.0
Huperzine −166.63 7.2
Ortho-7 −3764.00 4.0
Pyridostigmine −153.42 6.4
Ambenoniun −247.22 8.0
AChE inhibitor substrate −137.30 7.2
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Modelled BChE was docked with its ligand using the tool Hex. The energy values and R-values are retrieved and shown in Table 6. An energy value of −270.93 kcal mol−1 for Dibucaine showed good docking result with modelled BChE.

Table 6.

Docking Results for modelled BChE and its Ligand in kcal mol−1 (using Hex)

LIGANDS Etotal in kcal mol(-1) R-value In °A
Chlorpyrifos-oxon −186.55 21.6
1-analino-8-naphtalene sulfonic acid −192.87 21.6
Dibucaine −270.93 20.0
Procainamide −214.37 20.0
Benzoylcholine −208.92 18.4
Propionylthiocholine −172.31 16.8
Acetylthiocholine −154.31 12.0
Di alkyl phenyl phosphates −174.23 21.6
Tetra ethyl ammonium −142.29 17.6
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DISCUSSION

The functional properties of proteins are determined by their three-dimensional structures, self assemble into advanced structures is chargeable for their dominant role in biological functions. The range of life within the contemporary world has been generated by evolutionary processes functioning on these core processes through millions years. The generation of this diversity has fairly often resulted from the difference of existing biochemical components to new biological components instead of the event of essentially new biochemical technology [38, 39]. BChE deficient individuals are typically healthy with no apparent signs of diseases [40].

There is lot of evidence that supports cholinergic mechanisms modulate learning and memory formation [41, 42]. The strength and influence of any neural system on behavioral output is modulated by internal secretion standing by selective lesions of hippocampus, striatum, and also the amygdaloid nucleus [43]. AChE and BChE contains multiple potential substrate binding areas, is responsible for caparison and delivery of Benzoylcholine to the active site [44, 45]. Individuals with regular BChE and AChE have a high intravenous anesthetic range [46]. Obidoxime, trimedoxime, pralidoxime (2-PAM) and asoxime (HI-6) are commercial drugs containing the oxime group are able to split organophoshorus moiety from the the active site resulting in liberation and enzyme reactivation. All the chosen molecules have shown negative energies and therefore will target in control the AChE and BChE levels in humans. Rivastigmine and donepezil controls brain acetylcholine levels has shown by experimentation by Naik et al., in 2009 in acetylcholinesterase-deficient mice [47].

Huperzine and AChE inhibitor substrates from Huperzia cf chamaeleon and Huperzia reflexa, Lycopodium clavatum subsp. Clavatum showed strong AChE inhibition [48, 49]. Galanthamine, an alkaloid derivative phytocompound isolated from snowdrop (Galanthus nivalis L.) [50] and Huperzine A, a naturally occurring sesquiterpene alkaloid compound isolated from Huperzia serrata (Thunb.) Trev., [50, 51] are the latest anticholinesterase drugs using against AD. Plant derived alkaloids like galanthamine, huperzine A and rivastigmine are known for their AChE inhibitory activity [52, 53]. Ambenonium, an old AChE inhibitor [54, 55], Ortho-7, a more efficient reactivator than HI-6 [56], Donepezil [57] and Pyridostigmine [56] has shown good activity against AChE. The present report has also been proved good with high binding affinity of AChE with Ortho-7.

People with BChE deficiency are likely to be intolerant of standard doses of the anti-Alzheimer’s drugs such as huperzine A and donepezil [58]. Chlorpyrifosoxon [59], 1-anilino-8-naphthalene sulfonic acid [60], Dibucaine, Procainamide, Benzoylcholine, Propionyl thicholine, Acetyl thiocholine, Dialkylphenylphosphates, Tetra ethyl ammonium are virtually screened and selected for the activity against BChE [61. 62]. The present report has also been proved good with high binding affinity of BChE with Dibucaine as drug to AD and D2M.

BChE, resembling AChE, is typically associated with catalyzing the hydrolysis of the neurotransmitter acetylcholine (ACh) and yield choline and acetic acid. BChE has a clear role in neural functions in the co-regulation of cholinergic and non-cholinergic neurotransmission [63]. Cerebrovascular disease is thought to decrease the threshold at which amyloid deposition causes the manifestations of AD that starts with memory impairment, reaching the threshold of mild cognitive impairment, and eventually dementia [64].

Protein interactions between AChE and BChE with other proteins were retrieved using STRING, HPRD and Pathway linker database. Protein-Protein interactions in molecular disorders have been already studied using STRING and HPRD in MAPK pathway [65]. The AChE and BChE proteins [66, 67, 68] showed interaction with few other proteins like COLQ, NGF etc. The phosphomotifs for the protein AChE and BChE were also be retrieved and studied for better understanding of relationships in homologous sequences.

AChE and BChE are regular targets of a large number of toxins and understanding of cholinesterase structure and the biological mechanisms of inhibition is necessary for novel drug development. Dibucaine, Ortho-7 and HI-6 are predicted as good targets for AChE and BChE proteins and can control metabolic syndromes in humans.

The work concludes hat Cholinesterases play an important role in the human system. Humans in the present generation are exposing toxic products in body, in the form of pesticides and microbial toxins in foods. AchE and BChE are the proteins involved in ageing disease like Alzheimer’s and D2M. The present study shows the functional studies using phylogeny and protein interactions. The virtual molecular screening of drugs on AChE and BChE has been studied using docking methods.

Table 1.

Modelled AChE and its Ligands Docking (AutoDock)

Properties Huperzine Rivastigmine Ambenonium Ortho-7 Donepezil Pyrid Ostigm Ine Galan Thamine AChE inhibitor substrate HI-6
Binding-energy −3.73 −3.9 0.96 −3.3 −4.58 −3.36 −4.29 −2.12 −6.76
Ligand-efficiency −0.21 −0.22 0.03 −0.13 −0.16 −0.26 −0.15 −0.21 −0.32
Inhib-constant 1.83 1.38 - 3.79 436.93 3.44 711.8 28.14 11.12
Inhib-constant–units Mm Mm - Mm Um Mm Um Mm Um
Intermol-energy −3.73 −5.39 −3.81 −6.58 −6.37 −3.96 −6.08 −3.31 −8.55
Vdw-hb-disolve-energy −3.7 −5.33 −3.79 −6.6 −6.29 −3.95 −5.97 −3.28 −8.51
Electrostatic-energy −0.04 −0.06 −0.02 0.01 −0.08 0.0 −0.12 −0.03 −0.04
Total-energy 0.0 −0.17 115.77 1.01 −0.35 −0.29 0.52 −0.11 3.84
Torsional-energy 0.0 1.49 4.77 3.28 1.79 0.6 1.79 1.19 1.79
Unbound-energy 0.0 −0.17 115.77 1.01 −0.35 −0.29 0.52 −0.11 3.84
ClRMS 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0
RefRMS 38.75 35.96 35.82 36.13 33.66 35.11 35.78 34.9 212.67
Rseed1 None None None None None None None None None
Rseed2 None None None None None None None None None
Active site of protein ARG577 TRP571 PHE575 PHE575 PHE575 PHE575 PHE575 LYS572 TYR72
TYR581 GLY574 TRP578 TRP578 TRP578 TRP578 TRP578 TRP571 VAL73
GLY574 PHE575 ARG577 ARG577 ARG577 TRP571 TYR581 PHE575 TYR124
TRP578 ARG577 TYR581 TYR581 TYR581 TRP571 SER125
TRP578 TRP571 TRP571 TRP571 GLY574 ASP74
GLY120
SEN203
TRP86
GLU202
HIS447
Open in a new tab

Acknowledgments

Author would like to thank management and staff of GITAM University Visakhapatnam, India for their kind support in bringing out the above literature and providing lab facilities.

Footnotes

Conflict of interest

The authors do not have any conflict(s) of interest

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