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In silico Docking Study of Active Constituents Identified
in Morinda Citrifolia Linn as Enzyme targets of
Alzheimer's Disease
J. Srikanth1, S. Kavimani2, and C. Uma Maheswara Reddy1
1Department of Pharmacology, Faculty of Pharmacy, Sri Ramachandra University, Porur, Chennai – 600 116, Tamil Nadu, India 2Dept of Pharmacology, Mother Theresa Post Graduate and Research Institute of Health Sciences, Puducherry - 605006, India Abstract - Alzheimer's disease (AD) or Senile Dementia of 1 Introduction
the Alzheimer Type (SDAT) is an irreversible but
citrifolia progressive neurodegenerative disorder caused by the loss commercially as Noni grows widely throughout the Pacific of neurons and synapses in the cerebral cortex and certain and is one of the most significant sources of traditional sub-cortical regions. Cholinesterases (ChEs) are family of medicines among Pacific island societies. A number of enzymes that share extensive sequence homology (65%). phytoconstituents has been identified in the fruits of ChEs in vertebrates have been classified into two types, Morinda citrifolia such as Allantoin, Octanoic acid, acetylcholinesterase (AChE) and butyrylcholinesterase Vanillin, n Decanoic acid, 1, 2-dihydroxy-anthraquinone, (BChE), on the basis of distinct substrate specificities and Hexoic acid, Isoscopoletin, Morindin, 1, 3-dimethoxy- inhibitor sensitivities which serves as enzyme targets for AD. anthraquinone, quercetin , scopoletin , kaempferol , The search can be focused on plant natural products that Asperuloside,, may offer treatment for AD than currently used drugs. As an Dehydromethoxygaertneroside, (-)-pinoresinol, attempt to identify such natural alternates with bisdemethylpinoresinol, (+)-3,3'-bisdemethyltanegool , cholinomimetic & neuroprotective activities, a set of 22 Borreriagenin, Deacetylasperuloside, isoamericanoic acid A compounds identified from Morinda citrifolia fruit juice was [1-5]. Traditional synthesis of a series of new compounds docked against human AChE (PDB ID:1B41) / utilizing combinatorial chemistry and high-throughput Butyrylcholine esterase (PDB ID: 2PM8) enzymes retrieved screening can be carried out at high cost and also are time from protein data bank using Molegro Virtual Docker consuming whereas on the other hand, docking various (MVD). Among the compounds analysed, five compounds, ligands to the protein of interest followed by scoring to ,3,3'- determine the affinity of binding and to reveal the strength bisdemethylpinoresinol, (-)-pinoresinol, isoamericanoic acid of interactions has become increasingly important in the A, quercetin are docked with a MolDock score of -124.227, contest of drug discovery. As the extracts and fruit juice of -115.403, -107.812, -106.993, -106.634 respectively for M.citrifolia have been shown to possess neuroprotective AChE and (+) -3,3'-bisdemethyltanegool, (-)-pinoresinol, against alzheimer's disease in some earlier studies [6, 7], it americanin 3,3'- was considered worthwhile to study the interaction of bisdemethylpinoresinol are docked with a MolDock score - phytoconstituents identified with both AChE / BChE and 132.26, -126.487, -115.81, -114.994, -109.8 respectively for compared with existing drug molecules by molecular BChE and all these phytoconstituents satisfies Lipinski's docking studies. rule of ‘5' for drug likeliness property. The compounds were identified as potent and selective inhibitors of AChE/BChE compared to currently available drug molecules, tacrine, rivastigmine and huperazine A which showed inhibitory activity for AChE (MolDock score was -69.7799, -95.5779 & -72.1161) and for BChE (MolDock score was -70.3026, -91.32 & -68.5103). These phytoconstituents from M. citrifolia may serve as potential lead compound for developing new anti- alzheimer drug. Keywords: Morinda Citrifolia, Docking, Acetylcholine
esterase, Butyrylcholine esterase.
2 Materials & Methods
2.4 Parameters for docking search algorithms
2.1 Preparation of Ligand
2.4.1 MolDock Optimizer
We have collected the structures of phytoconstituents of M.citrifolia and currently available drug molecules from In MVD, selected parameters were used for the guided PubChem database (http://puBChEm.ncbi.nlm.nih.goc/).Our differential evolution algorithm: number of runs =5 by AChE/ BChE inhibitor database comprises 22 bioactive checking constrain poses to cavity option), population compounds from M. citrifolia. The inhibitors were converted size=50, maximum interactions =2000,cross over rate=0.9,and to .pdb format and optimized by means of ligand preparation scaling factor=0.5.Ao variance-based termination scheme was using default settings in Molegro Virtual Docker (MVD- selected rather than root mean square deviation(RMSD).To 2010,4.2.0) [8]. The collected structures (ligands) were ensure the most suitable binding mode in the binding cavity, prepared for further studies. Pose clustering was employed, which lead to multiple binding modes. 2.2 Preparation of receptor
2.5 Parameters for scoring functions
The X-ray crystal co-ordinates of AChE (PDB ID: 1B41) & BChE (PDB ID: 2PM8) were retrieved from protein data 2.5.1 MolDock score
bank. Since ChEs have their crystal structure in a state that
represent the pharmacological target for the development of They ignore-distant-atoms option was used to ignore new drugs to cure AD, these two PDBs were selected for atoms far away from the binding site. Additionally, hydrogen modeling studies. It is well known that PDB files often have bond directionality was said to check whether hydrogen poor or missing assignments of explicit hydrogens, and the bonding between potential donors and acceptors can occur. PDB file format cannot accommodate bond order information. The binding site on the protein was defined as extending in X, Therefore, proper bonds, bond orders, hybridization and Y & Z directions around the selected cavity with a radius of 25 charges were assigned using the MVD. The potential binding Angstroms. sites of both ChE receptors were calculated using the built-in
cavity detection algorithm implemented in MVD. The search 2.6 Results & Discussions
space of the simulation exploited in the docking studies was
studied as a subset region of 25.0 Angstroms around the active 2.6.1 Binding mode
side cleft. The water molecules are also taken in to The active site of AChE& BChE is subdivided into consideration and the replaceable water molecules were given several subsites; the esteratic subsite, also called the catalytic a score of 0.50. triad (CT, Ser200, His440, Glu327), oxyanion hole (OH, Gly118, Gly119, Ala201), anionic subsite (AS, Trp84, 2.3 Molecular docking
Tyr121, Glu199, Gly449, Ile444), acyl binding pock et (ABP, Trp233, Phe288, Phe290, Phe292, Phe330, Phe331) and 2.3.1 MVDs docking search algorithms and scoring peripheral anionic subsite (PAS, Asp72, Tyr121, Ser122,
functions
Trp279, Phe331, Tyr334) are buried at the bottom of a 20 A Ligand docking studies were performed by MVD, which deep aromatic cleft . It was found out by ligand energy has recently been introduced and gained attention among inspector that the phytoconstituents as well as the drug medicinal chemists. MVD is a fast and flexible docking molecules were able to bind to the any one of the sub sites of program that gives the most likely conformation of ligand AchE & BchE. binding to a macromolecule. MolDock software is based on a
new heuristic search algorithm that combines differential 2.6.2 Predicted ADME properties
evolution with a cavity prediction algorithm [9]. It has an interactive optimization technique inspired by Darwinian We analysed 22 physically relevant properties of Evolution Theory (Evolutionary Algorithms - EA), in which a bioactive compounds from Morinda citrifolia, among which population of individuals is exposed to competitive selection were molecular weight, H-bond donors, H-bond acceptors and that weeds out poor solutions. Recombination and mutation Log P (octanol/water), according to Lipinski's rule-of-five are used to generate new solutions. The scoring function of (Tables 1 & 2) by EPI suite software [13]. Lipinski's rule of 5 MolDock is based on the Piecewise Linear Potential (PLP), is a thumb to evaluate drug likeness, or determine if a chemical which is a simplified potential whose parameters are fit to compound with a certain pharmacological or biological activity protein-ligand structures and a binding data scoring function has properties that would make it a orally active drug in [10, 11] that is further extended in GEMDOCK (Generic humans. The rule describes molecular properties important for Evolutionary Method for molecular DOCK) [12] with a new a drug's pharmacokinetics in the human body, including its hydrogen bonding term and charge schemes. ADME. However, the rule does not predict if a compound is pharmacologically active. In this study, all the showed allowed values for the properties analysed and exhibited drug-like characteristics based on Lipinski's rule-of-five. Four compounds citrifolia Dehydromethoxygaertneroside, citrifolinin B, Asperuloside & Morindin deviate Lipinski's rule-of-five even though they had the maximum Moldock score [14, 15]. 2.7 Tables
Table 1: Top 1 pose for each ligand based on Moldock score and applying Lipinski's rule of 5 on AChE (PDB ID: 1B41)
Molecular
Acceptor
Deacetylasperuloside (+)-3,3'-bisdemethyltanegool
-124.227
-94.7819
-10.4588
192.16812
3,3'-bisdemethylpinoresinol
-115.403
-93.4557
-5.44479
268.26408
-107.812
-83.2098
192.16812
isoamericanoic acid A -106.993
-84.3006
-8.97877
116.15828
quercetin
-106.634
-81.4073
328.31604
Rivastigmine
-95.5779
-75.4124
-1.78946
n- Decanoic acid 1, 2-dihydroxy-anthraquinone Huperazine A
-72.1161
-58.8041
-2.14292
1, 3-dimethoxy-anthraquinone -69.7799
-64.0732
234.7246
Table 2: Top 1 pose for each ligang based on Moldock score and applying Lipinski's rule of 5 on BChE (PDB ID: 2PM8)
Molecular
Acceptor
(+)-3,3'-bisdemethyltanegool
-63.2503
-12.2203
348.3472
-126.487
-80.7681
358.3851
americanin A
-86.7568
-5.72732
Deacetylasperuloside
-114.994
-81.5302
-11.4067
3,3'-bisdemethylpinoresinol
-81.0274
-13.6929
330.3319
isoamericanoic acid A Rivastigmine
-69.1692
1, 2-dihydroxy-anthraquinone 1, 3-dimethoxy-anthraquinone -70.3026
-55.7944
-1.46667
234.7246
Huperazine A
-68.5103
-57.8567
-0.44966
continuous spaces; Technical report. International Computer 3 Conclusions
Science Institute: Berkley, CA; 1995. [10] Gehlhaar DK, Verkhivker G, Rejto PA, Fogel DB, Molecular docking studies revealed that the potential of Fogel LJ, Freer ST: Docking conformationally flexible small plant phytoconstituents of Morinda citrifolia to inhibit ChE'S molecules into a protein binding site through evolutionary was attributable to cumulative effects of strong H2-bonds, programming. In Proceedings of the Fourth International cationin-π,π-π interactions and hydrophobic interactions.A Conference on Evolutionary Programming: 1-3 March 1995; selected San Diego Edited by: John R McDonnell, Robert G Reynolds, phytoconstituents drugs/molecules David B Fogel. MIT Press; 1995:615-627. (Rivastigmine, Tacrine, Huperazine A) was found to have [11] Gehlhaar DK, Bouzida D, Rejto PA, Eds: Fully better affinity.This study has revealed the fact that herbal automated and rapid flexible docking of inhibitors covalently medicinal plants identified in Indian systems of Medicine are bound to serine proteases. In Proceedings of the Seventh more efficacious compared to allopathic system of medicine International Conference on Evolutionary Programming: 25-27 but it draws back due to the difficulty in standardization and March 1998; San Diego Edited by: William Porto V, lack of literature. These modern techniques and analysis will Saravanan N, Donald E Waagen, Eiben AE. Springer; be helpful in evaluating and documenting these herbal 1998:449-461. compounds identified in the Indian system of medicine as [12] Yang JM, Chen CC: GEMDOCK: A generic potent compounds for treatment for various ailments. evolutionary method for molecular docking. Proteins 2004, 55:288-304. 4 References
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