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ORIGINAL ARTICLE
Year : 2017  |  Volume : 13  |  Issue : 51  |  Page : 512-518  

Molecular docking analysis of phytic acid and 4-hydroxyisoleucine as cyclooxygenase-2, microsomal prostaglandin E synthase-2, tyrosinase, human neutrophil elastase, matrix metalloproteinase-2 and -9, xanthine oxidase, squalene synthase, nitric oxide synthase, human aldose reductase, and lipoxygenase inhibitors


1 Department of Nutrition and Dietetics, Faculty of Medicine and Health Sciences, Universiti Putra Malaysia, Serdang, Selangor, Malaysia; Bio Waste Management Laboratory, Vel Tech Technology Incubator, Veltech Dr. RR & Dr. SR University, 400 Feet Outer Ring Road, Avadi, Chennai, Tamil Nadu, India
2 Faculty of Pharmacy, Universiti Kebangsaan Malaysia, Jalan Raja Muda Abdul Aziz, Kuala Lumpur, Malaysia
3 Department of Nutrition and Dietetics, Faculty of Medicine and Health Sciences; Laboratory of Molecular Biomedicine, Institute of Bioscience, Universiti Putra Malaysia, Serdang, Selangor, Malaysia

Date of Submission12-Apr-2016
Date of Acceptance11-Jul-2016
Date of Web Publication11-Oct-2017

Correspondence Address:
Norhaizan Mohd Esa
Department of Nutrition and Dietetics, Faculty of Medicine and Health Sciences, Universiti Putra Malaysia, 43400 Serdang, Selangor
Malaysia
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/pm.pm_195_16

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   Abstract 


Background: The phytoconstituents phytic acid and 4-hydroxyisoleucine have been reported to posses various biological properties. Objective: This prompted us to carry out the docking study on these two ligands (phytic acid & 4-hydroxyisoleucine) against eleven targeted enzymes. Materials and Methods: Phytic acid & 4-hydroxyisoleucine were evaluated on the docking behaviour of cyclooxygenase-2 (COX-2), microsomal prostaglandin E synthase-2 (mPGES-2), tyrosinase, human neutrophil elastase (HNE), matrix metalloproteinase (MMP 2 and 9), xanthine oxidase (XO), squalene synthase (SQS), nitric oxide synthase (NOS), human aldose reductase (HAR) and lipoxygenase (LOX) using Discovery Studio Version 3.1 (except for LOX, where Autodock 4.2 tool was used). Results: Docking and binding free energy analysis revealed that phytic acid exhibited the maximum binding energy for four target enzymes such as COX-2, mPGES-2, tyrosinase and HNE. Interestingly, we found that 4-hydroxyisoleucine has the potential to dock and bind with all of the eleven targeted enzymes. Conclusion: This present study has paved a new insight in understanding 4-hydroxyisoleucine as potential inhibitor against COX-2, mPGES-2, tyrosinase, HNE, MMP 2, MMP 9, XO, SQS, NOS, HAR and LOX.
Abbreviations used: COX-2: Cyclooxygenase-2, mPGES-2: Microsomal prostaglandin E synthase-2, HNE: Human neutrophil elastase, MMP-2 and -9: Matrix metalloproteinase-2 and -9, XO: Xanthine oxidase, SQS: Squalene synthase, NOS: Nitric oxide synthase, HAR: Human aldose reductase, LOX: Lipoxygenase, ADME: Absorption, distribution, metabolism, and excretion, TOPKAT: Toxicity Prediction by Computer-assisted Technology.

Keywords: 4-hydroxyisoleucine, cyclooxygenase-2, microsomal prostaglandin E synthase-2, molecular docking, phytic acid, tyrosinase


How to cite this article:
Narayanaswamy R, Wai LK, Esa NM. Molecular docking analysis of phytic acid and 4-hydroxyisoleucine as cyclooxygenase-2, microsomal prostaglandin E synthase-2, tyrosinase, human neutrophil elastase, matrix metalloproteinase-2 and -9, xanthine oxidase, squalene synthase, nitric oxide synthase, human aldose reductase, and lipoxygenase inhibitors. Phcog Mag 2017;13, Suppl S3:512-8

How to cite this URL:
Narayanaswamy R, Wai LK, Esa NM. Molecular docking analysis of phytic acid and 4-hydroxyisoleucine as cyclooxygenase-2, microsomal prostaglandin E synthase-2, tyrosinase, human neutrophil elastase, matrix metalloproteinase-2 and -9, xanthine oxidase, squalene synthase, nitric oxide synthase, human aldose reductase, and lipoxygenase inhibitors. Phcog Mag [serial online] 2017 [cited 2021 Oct 26];13, Suppl S3:512-8. Available from: http://www.phcog.com/text.asp?2017/13/51/512/216335



Summary

  • 4-hydroxyisoleucine has the potential to dock and bind with all 11targeted enzymes such as.(cyclooxygenase-2.[COX-2], microsomal prostaglandin E synthase-2.[mPGES-2], tyrosinase, human neutrophil elastase.[HNE], matrix metalloproteinase.[MMP-2 and-9], xanthine oxidase, squalene synthase, nitric oxide synthase, human aldose reductase, and lipoxygenase)
  • Moreover, docking studies and binding free energy calculations revealed that phytic acid exhibited the maximum binding energy for four target enzymes such as COX-2, mPGES-2, tyrosinase, and HNE; however, for other six target enzymes, it fails to dock.



   Introduction Top


Phytic acid is abundant in nature (especially in plants). It accounts for 1%–5% weight of edible cereals, legumes, nuts, oil seeds, and tubers. Although it is well known as antinutrient agent, in recent years, phytic acid has been reported to possess a number of biological activities such as antibacterial, antidiabetic, anti-inflammatory, anticarcinogenic, antioxidant, antiangiogenic, antiulcer, antiviral, hypoallergenic, hypolipidemic, immunomodulation, and neuroprotection.[1],[2]

Various reports have revealed that fenugreek (Trigonella foenum-graecum) seeds' extract exhibits anti-inflammatory activity, as well as lower blood glucose and cholesterol levels in humans and experimental animals.[3],[4],[5] 4-hydroxyisoleucine is a unique amino acid isolated and identified from fenugreek (T. foenum-graecum) seeds. It accounts for about 80% of the total amino acid within the seeds. Further two diastereoisomers of 4-hydroxyisoleucine have been reported from fenugreek seeds, the major one is (2S, 3R, 4S) configuration and another (minor) one is (2R, 3R, 4S) configuration, respectively. (2S, 3R, 4S) configuration of 4-hydroxyisoleucine has been reported as an antidiabetic agent.[6] 4-hydroxyisoleucine has been reported as hepatoprotective agent [7] and also reported to inhibit palmitate-induced reactive oxygen species generation.[8] Therefore, these two phytoconstituents, namely, phytic acid and 4-hydroxyisoleucine were selected to be evaluated in this study on the docking behavior of cyclooxygenase-2 (COX-2), microsomal prostaglandin E synthase-2 (mPGES-2), tyrosinase, human neutrophil elastase (HNE), matrix metalloproteinase (MMP-2 and -9), xanthine oxidase (XO), squalene synthase (SQS), nitric oxide synthase (NOS), human aldose reductase (HAR), and lipoxygenase (LOX) with investigation on the enzymes putative binding sites using Discovery Studio version 3.1 (except for LOX, where Autodock 4.2 [Scripps Research Institute, San Diego, USA] tool was used).


   Materials And Methods Top


In this section, ligand preparation, target protein identification and preparation, molecular descriptors calculation, absorption, distribution, metabolism, and excretion (ADME), and Toxicity Prediction by Komputer-assisted Technology (TOPKAT) analysis were carried out according to the previously reported method [9] as briefly stated below.

Ligand preparation

Chemical structures of the ligands, i.e., (i) phytic acid (ID 16735966) and (ii) 4-hydroxyisoleucine (CID2773624) were downloaded from ChemSpider (www.chemspider.com) and PubMed (www.pubmed.com) databases. Both the ligands were drawn in ChemBioDraw Ultra 12.0 (www.cambridgesoft.com), and subsequently, molecular mechanics 2 minimization of ligands was carried out using ChemBio3D Ultra 12.0 (PerkinElmer, Waltham, USA) (molecular mechanics (MM2)). Thus, these energy-minimized ligands (structures) were employed for Autodock 4.2, whereas in the case of CDOCKER inbuild ligand preparation protocol (Accelrys, San Diego, USA) was adopted.

Target protein identification and preparation

The three-dimensional protein structures of the COX-2 (PDB ID: 3 LN1 with resolution of 2.40 Å), mPGES-2 (PDB ID: 1Z9H with resolution of 2.60 Å), tyrosinase (PDB ID: 2Y9W with resolution of 2.30 Å), HNE (PDB ID: 1H1B with resolution of 2.00 Å), MMP-2 (PDB ID: 1QIB with resolution of 2.80 Å), MMP-9 (PDB ID: 4H1Q with resolution of 1.59 Å), XO (PDB ID: 3NRZ with resolution of 1.80 Å), SQS (PDB ID: 3ASX with resolution of 2.00 Å), NOS (PDB ID: 4NOS with resolution of 2.30 Å), HAR (PDB ID: 1US0 with resolution of 0.66 Å), and LOX (PDB ID: 1JNQ with resolution of 2.10 Å) were retrieved from the Research Collaboratory for Structural Bioinformatics Protein Data Bank (PDB) (Anonymous, www.rcsb.org). A chain of all proteins (except for XO and COX-2, where C chain; mPGES-2, where A, B, C, and D chains; and tyrosinase, where A and B chains) was preprocessed separately by deleting other chains (B, C, and D), ligand, as well as the crystallographically observed water molecules (water without hydrogen bonds). All the proteins above mentioned were prepared using UCSF Chimera software (www.cgi.ucsf.edu/chimera) for Autodock 4.2, whereas in the case of CDOCKER inbuild protein preparation protocol (Accelrys, San Diego, USA) was adopted.

Molecular descriptors calculation

Molinspiration online database was used for the two selected ligands to calculate thirteen descriptors (www.molinspiration.com) which are logP, polar surface area, molecular weight (MW), number of atoms, number of O or N, number of OH or NH, number of rotatable bonds, volume, drug-likeness including G-protein-coupled receptors ligand, ion channel modulator, kinase inhibitor, and nuclear receptor ligand, and the number of violations to Lipinski's rule.

Absorption, distribution, metabolism, and excretion and Toxicity Prediction by Komputer-assisted Technology analysis

Both ADME and TOPKAT analyses were performed using Discovery Studio ® 3.1 (Accelrys, San Diego, USA). ADME analysis was performed using six descriptors such as human intestinal absorption, aqueous solubility, blood–brain barrier, cytochrome P450 2D6, plasma protein binding, and hepatotoxicity. As for the TOPKAT analysis, five descriptors were used which includes aerobic biodegradability (AB), Ames mutagenicity, ocular irritancy, skin irritancy, and skin sensitization.

Docking studies

Docking studies were performed on the protein crystal structures of COX-2, mPGES-2, tyrosinase, HNE, MMP-2, MMP-9, XO, SQS, NOS, and HAR obtained from PDB using the CDOCKER protocol under the protein–ligand interaction section in Discovery Studio ® 3.1 (Accelrys, San Diego, USA). In general, CDOCKER is a grid-based molecular docking method that employs CHARMM force fields. Protein was first held rigid while the ligands were allowed to flex during the refinement. Two hundred random ligand conformations were then generated from the initial ligand structure through high-temperature molecular dynamics followed by random rotations, refinement by grid-based (GRID I) simulated annealing, and a final grid-based or full force field minimization.[10] In this experiment, the ligand was heated to a temperature of 700 K in 2000 steps, and the cooling steps were set in 5000 steps to 300 K with the grid extension set to 10 Å. Hydrogen atoms were added to the structures, and all ionizable residues were set at their default protonation state at a neutral pH. For each ligand, top ten ligand binding poses were ranked according to their CDOCKER energies, and the predicted binding interactions were then analyzed, from which the best among the ten ligand binding poses were chosen and carried out in situ ligand minimization using a standard protocol.

Docking was performed using Autodock 4.2 version, in which combined energy evaluation through precalculated grids of affinity potential employing various search algorithms to find the suitable binding position for a ligand on a given protein (LOX). All rotatable bonds in the ligands were kept free to allow flexible docking. Grid size was set to 60 × 60 × 60 grid points (x, y, and z), with spacing between grid points kept at 0.375 Å. The Lamarckian genetic algorithm was chosen to search for the best conformers. Standard docking protocol was applied. One hundred independent docking runs for each ligand were generated using genetic algorithm search.[11]


   Results and Discussion Top


Phytic acid and 4-hydroxyisoleucine were the two ligands selected for the present study; it could be beneficial to know the physicochemical and drug-likeness properties of these ligands before carry out docking studies. Lipinski's rule of five was applied to know the above said properties and further helps to determine whether a lead compound having a certain pharmacological or biological activity could be made into an orally active drug for human.[12] Violation of the Lipinski's rule of five is when logP >5, MW >500, number of N, O (hydrogen bond acceptor) >10, number of OH and NH (hydrogen bond donor) >5, and number of rotatable bond (rotb) >15. In the present study, 4-hydroxyisoleucine showed no violation with respect to thumb rule of five (Lipinski's rule of five). On the other hand, phytic acid showed three violations as given in [Table 1]. With regard to drug-likeness score, if the score is >0 is active, −5.0–0.0 is moderate active, and <−5.0 is inactive.[13] Phytic acid showed active bioactivity score (>0) toward all descriptors, whereas 4-hydroxyisoleucine has shown active bioactivity score toward two descriptors as shown in [Table 2]. ADME prediction is also required before carry out docking studies and which is now commonly acceptable in early stage of drug discovery, drug screening, and drug design, owing to its unique characteristic nature.[14] [Table 3] shows the ADME profile of the two selected ligands, wherein phytic acid was predicted to have very poor intestinal absorption and hepatotoxic effect. On the other hand, 4-hydroxyisoleucine was predicted to have good intestinal absorption. The toxicity profile of the two ligands as depicted in [Table 4] shows that phytic acid was nondegradable toward AB nature, and both the ligands were predicted to have ocular/eye irritancy effect in humans.
Table 1: Molecular physicochemical descriptors analysis on two ligands using Molinspiration online software tool

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Table 2: Bioactivity score of two ligands using Molinspiration online software tool

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Table 3: Absorption, distribution, metabolism, and excretion analysis of phytic acid and 4-hydroxyisoleucine

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Table 4: Toxicity prediction analysis of phytic acid and 4-hydroxyisoleucine

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COX is the key enzyme which catalyzes the conversion of arachidonic acid (AA) to prostaglandins. In human, COX exists in two isoforms; COX-1 is a constitutive enzyme, whereas COX-2 is an inducible enzyme. Cytokines and growth factors increase the expression of COX-2 mainly at inflammatory sites.[15] The docking studies and binding free energy reported in [Table 5] show that phytic acid had the highest interaction energy (−42.20 kcal/mol) with COX-2 and both ligands exhibited interaction with Glu539 amino acid residue of COX-2 as shown in [Table 5]. Phytic acid has been reported to suppress the COX-2 expression in azoxymethane -induced colon cancer cells.[16] Similarly, in the present study, phytic acid exhibited interaction with Glu350, Trp531, and Asn546 amino acid residues of COX-2; this finding was in good agreement with Khokra et al. report.[17] In the case of 4-hydroxyisoleucine, there is no available reported investigation for their COX-2 inhibitory activity.
Table 5: The interaction energy analysis of phytic acid and 4-hydroxyisoleucine with cyclooxygenase-2 using Discovery Studio® 3.1

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mPGES-2 has exhibited board substrate specificity and also expressed constitutively in a variety of human tissues. Interestingly, it is not induced by pro-inflammatory signals like that of mPGES-1.[18] Recently, mPGES-2 has been reported to play a protective role against different types of liver injury.[19] As for the docking studies and binding free energy calculations with mPGES-2, phytic acid exhibited the highest interaction energy (−56.21 kcal/mol), and both ligands showed interaction with Ser295 amino acid residue of mPGES-2 as shown in [Table 6]. Interestingly, phytic acid interacts with all the four chains (A, B, C, and D) of mPGES-2. In the present study, both ligands had potential to dock with mPGES-2; however, until now, there is no report available with regard to their docking studies.
Table 6: The interaction energy analysis of phytic acid and 4-hydroxyisoleucine with microsomal prostaglandin E synthase-2 using Discovery Studio® 3.1

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Tyrosinase is the key regulatory enzyme in melanin biosynthesis pathway that too particularly in the first two steps such as (i) tyrosine hydroxylation to 3, 4-dihydroxyphenylalanine (DOPA) and (ii) the oxidation of DOPA to dopaquinone.[20] The maximum interaction energy in the docking studies and binding free energy calculations with that of tyrosinase was exhibited by phytic acid (−33.26 kcal/mol), and 4-hydroxyisoleucine showed interaction with Pro14 amino acid residue of tyrosinase as shown in [Table 7]. Graf et al. have reported that phytic acid as inhibitor of mushroom tyrosinase,[21] this was good in agreement with the present finding. Previously, we reported L-cysteine as tyrosinase inhibitor using molecular docking;[22] similarly, in the present study, we again revealed another amino acid (4-hydroxyisoleucine) as tyrosinase inhibitor.
Table 7: The interaction energy analysis of phytic acid and 4-hydroxyisoleucine with tyrosinase using Discovery Studio® 3.1

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HNE is key enzyme which plays a major role in degenerative and inflammatory diseases, through proteolysis and extracellular matrix (ECM) components.[23] HNE is another target protein/enzyme which its docking studies and binding free energy calculations showed phytic acid having the maximum interaction energy (−47.59 kcal/mol). Interestingly, both ligands exhibited interaction with Phe192 and Ser195 amino acid residues of elastase as shown in [Table 8]. In the present study, both ligands showed interaction with Ser195 amino acid residue of HNE; this was good in agreement with previous reports.[23],[24]
Table 8: The interaction energy analysis of phytic acid and 4-hydroxyisoleucine with human neutrophil elastase using Discovery Studio® 3.1

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MMPs are a group of zinc-dependent endopeptidase which is capable of degrading ECM components, and among the MMPs family, MMP-2 and -9 were reported to be elevated in the pathological conditions such as inflammation, wound healing, cancer, and aging.[24] The docking studies and binding free energy reported in [Table 9] show that 4-hydroxyisoleucine had the highest interaction energy (−43.47 kcal/mol) with that of MMP-2, but phytic acid fails to dock with the MMP-2. 4-hydroxyisoleucine showed interaction with Ala165, His201, and Glu202 amino acid residues of MMP-2 as shown in [Table 9]. As for the docking studies and binding free energy calculations with MMP-9, 4-hydroxyisoleucine exhibited the highest interaction energy (−38.60 kcal/mol), but phytic acid fails to dock with the same. 4-hydroxyisoleucine exhibited interaction with Ala189 and Gln227 amino acid residues of MMP-9 as shown in [Table 10]. In the present study, 4-hydroxyisoleucine exhibited interaction with Ala165, His201, and Glu202 amino acid residues of MMP-2 and with Ala189 and Gln227 amino acid residues of MMP-9, respectively, this finding was in good agreement with previous reports.[9],[23] However, phytic acid fails to dock with the MMP-2 and -9 might due to the general poor binding phenomenon as reported by Akdogan et al.[25]
Table 9: The interaction energy analysis of phytic acid and 4-hydroxyisoleucine with matrix metalloproteinase-2 using Discovery Studio® 3.1

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Table 10: The interaction energy analysis of phytic acid and 4-hydroxyisoleucine with matrix metalloproteinase-9 using Discovery Studio® 3.1

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XO is the key enzyme which catalyzes the oxidation of hypoxanthine to xanthine and then to uric acid.[9] XO is another target protein/enzyme which its docking studies and binding free energy calculations showed 4-hydroxyisoleucine having the maximum interaction energy (−29.23 kcal/mol), but phytic acid fails to dock with the XO. Interestingly, 4-hydroxyisoleucine showed interaction with molybdenum-oxygen-sulfur (MOS) complex which is the key component in XO as shown in [Table 11]. In the present study, 4-hydroxyisoleucine showed interaction with Arg880, Thr1010, and MOS1328 amino acid residues of XO; this was in good agreement with the previous report.[9] However, phytic acid fails to dock with the XO might due to the general poor binding phenomenon as reported by Akdogan et al.[25]
Table 11: The interaction energy analysis of phytic acid and 4-hydroxyisoleucine with xanthine oxidase using Discovery Studio® 3.1

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SQS is the key enzyme involves in cholesterol biosynthesis pathway, and it is inhibition leads to direct decrease in cholesterol biosynthesis resulted in reduction of plasma cholesterol level.[9] The maximum interaction energy in the docking studies and binding free energy calculations with that of SQS was exhibited by 4-hydroxyisoleucine (−22.59 kcal/mol), but phytic acid fails to dock with the same. 4-hydroxyisoleucine exhibited interaction with Val175 and Gln212 amino acid residues of SQS as shown in [Table 12]. In the present study, 4-hydroxyisoleucine exhibited interaction with Val175 and Gln212 amino acid residues of SQS; this finding was in good agreement with the previous report.[9] However, phytic acid fails to dock with the SQS might due to the general poor binding phenomenon as reported by Akdogan et al.[25]
Table 12: The interaction energy analysis of phytic acid and 4-hydroxyisoleucine with squalene synthase using Discovery Studio® 3.1

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NOS is a family of enzymes that catalyze the production of nitric oxide from L-arginine. Nitric oxide is a key cellular signaling molecule which plays a vital role in various cellular processes.[9] The docking studies and binding free energy reported in [Table 13] show that 4-hydroxyisoleucine had the highest interaction energy (−24.66 kcal/mol) with that of NOS, but phytic acid fails to dock with the NOS. Interestingly, 4-hydroxyisoleucine does not interact with any amino acid residue of NOS. In the present study, phytic acid fails to dock with the NOS might due to the general poor binding phenomenon as reported by Akdogan et al.[25]
Table 13: The interaction energy analysis of phytic acid and 4-hydroxyisoleucine with nitric oxide synthase using Discovery Studio® 3.1

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HAR is the key enzyme which plays a major role in the development of secondary diabetic complications through polyol pathway, which follows the entry of excess glucose into the body.[26] HAR is another target protein/enzyme which its docking studies and binding free energy calculations showed 4-hydroxyisoleucine had the maximum interaction energy (−34.50 kcal/mol), but phytic acid fails to dock with the same. Interestingly, 4-hydroxyisoleucine showed interaction with six amino acid residues (Thr19, Trp20, Lys21, Asp43, Ser210, and Ile260) of HAR as shown in [Table 14]. Thus, the present finding was in good agreement with Umamaheswari et al. report.[27] However, phytic acid fails to dock with the HAR might due to the general poor binding phenomenon as reported by Akdogan et al.[25]
Table 14: The interaction energy analysis of phytic acid and 4-hydroxyisoleucine with human aldose reductase using Discovery Studio® 3.1

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LOXs are the class of oxidative enzymes, which catalyze the formation of hydroperoxy eicosatetraenoic acids (HPETEs) from AA. Moreover, these HPETEs are further reduced and transformed to form so-called eicosanoids.[28] The docking studies and binding free energy reported in [Table 15] show that 4-hydroxyisoleucine with the lowest binding energy (−5.15 kcal/mol) using Autodock 4.2, and interestingly, 4-hydroxyisoleucine exhibited interaction with three amino acid residues (Ser510, His513, and Gln716) of LOX. The present finding was in good agreement with the previous report.[29] Phytic acid showed very least binding energy (+42.57 kcal/mol) with LOX, which might due to unfavorable interactions phenomenon as reported by Castro et al.[30]
Table 15: The interaction energy analysis of phytic acid and 4-hydroxyisoleucine with lipoxygenase using Autodock 4.2

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   Conclusion Top


In the present study, it was found that 4-hydroxyisoleucine has the potential to dock and bind with all of the 11 targeted enzymes, whereas phytic acid failed to dock and bind with six enzymes except COX-2, mPGES-2, tyrosinase, HNE, and LOX. Hence, it is strongly suggested that the results of this study have paved better understanding of 4-hydroxyisoleucine as potential COX-2, mPGES-2, tyrosinase, HNE, MMP-2, MMP-9, XO, SQS, NOS, HAR, and LOX inhibitor in relation to the prevention of associated disorders of inflammation, hyperpigmentation, wound healing, hyperuricemia, hyperlipidemia, and hyperglycemia.

Acknowledgement

The author (Radhakrishnan Narayanaswamy) would like to thank the Research Management Center of Universiti Putra Malaysia, for the postdoctoral financial support.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
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    Tables

  [Table 1], [Table 2], [Table 3], [Table 4], [Table 5], [Table 6], [Table 7], [Table 8], [Table 9], [Table 10], [Table 11], [Table 12], [Table 13], [Table 14], [Table 15]



 

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