sanjeeva yarkala et al. journal of scientific research in ... · department of chemistry, sam...

Amit Chattree et al., J. Sci. Res. Phar. 2012, 1(3), 107-111

Journal of Scientific Research in Pharmacy 2012, 1(3) 107-111

Journal of Scientific Research in Pharmacy Research Article Available online through ISSN: 2277-9469

www.jsrponline.com

Virtual Screening of 4 -Benzylidene-Amino-4,5-Dihydro-2H-1,2,4-Triazole-5-one Derivatives and their Potential application on Aspergillus Flavus

Amit Chattree* and Neelottma Singh Department of Chemistry, Sam Higginbottom Ins titute of Agriculture , Technology & Sciences, (Formerly Allahabad Agricultural Institute)

(Deemed to be University), Allahabad – 211007.

Received on: 08-09-2012; Revised on: 08-09-2012; Accepted on: 13-09-2012

ABSTRACT

In silico metabolic pathway analysis is one of the approaches that can be used for the designing antifungal potent drug. Rati onal drug designing can perform for the development of the drug like molecule, it is also known as target based drug designing or structure based drug designing. The field of chemoinformatics has become a major part of the drug discovery pipeline playing a key role for validating drug ta rgets. By integrating data from many interrelated yet heterogeneous resources, information can help in understanding of complex biological processes and help to i mprove drug discovery. The determination of the 3-D properties of small molecules and macromolecular receptor, structure is the core activity in the efforts towards a better understanding of structural activity relationship. In the present work chemo-informatics was employed to obtain the effective antifungal agent amongs t derivatives of “4-benzylidene-amino-4,5 dihydro-2H 1,2,4 triazole-5” against Aspergillus flavus. The work has been performed insilico using NCBI { Database}, Cactus server for protein format conversion {Database}, Swiss model {Server}, Molegro Virtual Docker {Software}, Pharma algorithm {Database}. The results obtai ned demonstrate that the derivative with chloro substituents is effective antifungal agents against A.flavus. It shows that triazole containi ng Chloro substituent have potential

pharmacological properties.

Key words: Virtual screening, 4-Benzylidene-Amino-4,5-Dihydro-2H-1,2,4-Triazole-5-one, Aspergillus Flavus.

INTRODUCTION

In silico is an expression used to mean "performed on computer or via computer simulation”. To manage chemical information and to solve chemical problems, the use of computer and information of technology is termed as chemo-informati cs. These insilico techniques are used in pharmaceutical companies in the process of drug discovery [4]. Several five membered heterocyclic compound have been shown to be promising antimicrobial agents [8]. Nitrogen containing heterocycles are frequently found in privileged structures (pharmacophores) but their incorporation some times possess special problems (multistep se quences, lack of generality, preparation from acyclic precursors, etc). Consequently, the design and development of procedures for the generation of new heterocycles re ceives growing interest [3].

Triazole shows the therapeutic effects against Candida, Aspergillus, Histoplasma, Blastomyces and many more opportunistic fungi [28]. It was also reported that a large number of compounds containing a triazole ring also possess a moderate antiviral activity [7]. The therapeutic effects of compounds containing 1,3,4-thiadiazole and 1,2,4-triazole rings have been well studied for a number of pathological conditions including inflammation , pain or hypertension [7].

Moreover, the triazoles have attracted widespread attention due to their diverse applications as antibacterial, antimycobacterial, antimycotic, antifungal and antidepressant agents. Meanwhile, N-acylated aminoacids are known for their hepatoprotective and antimicrobial effects [31]. The importance of triazole derivatives lie in the field that these have occupied a unique position in heterocyclic chemistry du e to their antimicrobial activity [37]. Triazole is advantageous due to its broad range of application in the treatment of both superficial and systemic fungal infections and it also shows grea ter affinity for fungal rather than mammalian Cytochrome P-450 enzymes for ex. Fluconazole for treatment of Histoplasmosis [34]. The mode of action of triazole derivatives is based on the ergosterol biosynthesis pathway inhibition at different steps. Ergosterol is the major component of the fungal cell membrane. Its essential function is as a bioregulator of membrane fluidity, asymmetry

and integrity. Triazole antifungal drugs work by inhibition of the fungal

*Corresponding author: Amit Chattree Department of Chemistry, Sam Higginbottom Insti tute of Agricul ture , Technology & Sciences, (Formerly Allahabad Agricul tural Institute) (Deemed to be University), Allahabad – 211007 Mobile No. +91 9936448878, Fax-0532 2684012 *E-Mail: [email protected]

Cytochrome P450 14- α demethylase. This interrupts the conversion of lanosterol to ergosterol, a component of the fungal cell membrane. Cytochrome P450 constitutes a super family of enzyme protein which has a significant part in the bio-transforma tion of drugs as xenobiotics. CYP P450 metabolize majority of currently known pharmaceutical agents and can cause drug-drug interactions with co-administered drugs as well as unwanted side effects [10].

CYP P450 is a large and diverse group of enzyme containing heme prosthetic group. CYP is usually present in smooth endoplasmic

reticulum. Its function is to ca talyze the oxidation of organic substances.

RH + O2 + 2H+ + 2e- ROH + H2O

Where RH is an organic substances. CYP is identifiable in all living kingdom [34].

The effect of the herbicide 3-amino-1,2,4 triazole has been examined in the mold Neurospora crassa as an inhibitor of heme synthesis in rat liver. The activity may vary with the genus, but the fungal infections still remain a significant cause of morbidity and mortality despite advances in medicine and the emergence of new antifungal agents. Immunocompromised patients are particularly at risk of developing these infections, with Aspergillus sp. that are resistant to antifungal agents, making treatment options a concern [30].

The cell wall of pathogens contain mannoproteins, chitins, and α and β-glucans and plays an important role in protection, cell morphology, cell rigidity, metabolism, ion exchange and filtration, antigenic expression, primary interaction with the host and resistance to host cell-mediated immune function. Some mutation in the genes also confers resistance in fungus [28]. At cellular level resistance can be the result of replacement of a susceptible strain with a more resistant strain or the alteration of a endogenous strain to a resistant phenotype. Extensive use of antimicrobial drugs favors the emergence of resistant strains. It has been found that substituent attached to the triazole ring influences the biological activity of the drug against resistant strains. The combination of two or more heterocyclic and non heterocyclic systems enhances the biological profile many fold than its parent nuclei [5]. On substituting chlorine in the phenyl ring the activity gets enhanced many folds [13]. Antimicrobial activity of Mannich bases of 2,5 disubstituted 4 - thiazolidinones shows that ethyl group has more potential than phenyl group [1]. Electronic character of the triazole system also affects the activity of the drugs. Aldehyde, Aldoxime, Cyanoazole, generally improves the antibacterial activity. However amide, ester, amino, hydroxyl, alkoxy and alkyl substituent resulted in no improvement or loss in antibacterial activity [9].

mailto:[email protected]

http://en.wikipedia.org/wiki/Cytochrome_P450_14Î±-demethylase

http://en.wikipedia.org/wiki/Ergosterol



It had also been explained that electropositive effect of methyl group attached to the phenyl moiety shows favourable influence on the potency of the heterocyclic nuclei [31]. Genetics, age, stre ss, hormone, and other endogenous chemicals also influence drug metabolism. Additional influences on drug interaction include drug dosing issues and specific features [20]. Potential of drugs also depends on ADMET (Absorption, Distribution, Metabolism, Excretion and Toxicity) properties. Thus the identification of novel drug target and their inhibitors is a major challenge in the field of drug designing and development.

The antimicrobial identification using experimental techniques is invariably very expensive, requires extensive pains and labour. Therefore, in silico techniques, which have the power to cut down these unavoidable steps, would be valuable.

In the current study attempts have been made to do the insilico analysis of different effective triazole derivatives of 1,2,4 triazole and to

locate the novel drug target in three different fungi - Aspergillus flavus,

MATERIALS AND METHODS

Materials: Following databases, softwares & online servers were used

during the study: PDB {http://www.pdb.org} NCBI {Database: www.ncbi.nlm.nih.gov} Cactus server for protein forma t conversion {Databa se} Swiss model {Server :- http:/swissmodel.expasy.org} Molegro Virtual Docker {Software}

Pharma algorithm {Database}

Methodology:

Sequence retrieval Homology modeling

Generation of ligand library

Virtual screening of the ligand library for minimum energy calculation

In silico adme/tox analysis of drug like molecules

RESULTS AND DISCUSSION

Sequence Retrieval: The sequence of amino acids in 14-α sterol demethylase of

A.flavus was retrieved in FASTA format from NCBI.

WFPFIGSTISYGMDPYRFFFNCREKYGDIFTFY LLGKKTTVYLGTKGNDFILNGKLROVCAEEVYSPLTTPVFGRHVVYDCNAK

Homology Modeling: Homology based modeling of enzymes was done by Swiss

Model server [2] and the structural homologue, which was used as a template for this model, is 14-α sterol demethylase from Aspergillus flavus .

Fig. 1: Secondary structure of enzyme 14-α sterol demethylase (Cyp

P450) in Aspergillus flavus

Fig. 2: Amino acid sequence (residue) in 14-α sterol demethylase (Cyp P450) in Aspergillus flavus

Generation of Library of Triazoles: Ligand library was generated with the help of cactus server

(CADD groups) by changing the substituents and their positions in the

ring. Library is generated in mol 2 format 3D structure and properties of

the derivatives were tabulated as follows:

S. No. 3D Structure Properties

4.3.3(a)

Molecular Weight : 352.387 Molecular Formula: C19H20N4O3

Smile: CCOc3cc(C=Nn2c(c1ccccc1)nn (C)c2=O)ccc3OC IUPAC Name: 1-methyl-3-phenyl-4- (3-ethoxy-4-methoxybenzylidenamino) -4,5-dihydro-1H-1,2,4-triazole-5-one Heavy atoms: 26

Torsion 6

Nitrogen Carbon Sulphur Oxygen Chlorine Fluorine Bromine

http://www.pdb.org/

http://www.ncbi.nlm.nih.gov/



4.3.3(b)


Smile: CCOc3cc(C=Nn2c(Cc1ccccc1) nn(C)c2=O)ccc3OC IUPAC Name: 1-methyl-3-benzyl-4- (3-ethoxy-4-methoxybenzylidenamino) -4,5-dihydro-1H-1,2,4-triazole-5-one Heavy atoms: 27 Torsion 7

4.3.3(c)


Smile: CCOc3cc(C=Nn2c(Cc1ccc(Cl)cc1) nn(C)c2=O)ccc3OC IUPAC Name:1-methyl-3-chloro benzyl- 4-(3-ethoxy-4-methoxybenzylidenamino)-4,5-dihydro-1H-1,2,4-triazole- 5-one Heavy atoms: 28 Torsion 7

4.3.3(d)


Smile: CCOc2cc(C=Nn1c(C)nn(C )c1=O)ccc2OC IUPAC Name: 1-methyl-3-ethyl-4 -(3-ethoxy-4-methoxybenzylidenamino) -4,5-dihydro-1H-1,2,4-triazole-5-one Heavy atoms: 22 Torsion 6

4.3.3(e)


Smile: CCOc2cc(C=Nn1c(C)nn (C)c1=O)ccc2OC IUPAC Name: 1-methyl-3-methyl-4- (3-ethoxy-4-methoxybenzylidenamino) -4,5-dihydro-1H-1,2,4-triazole-5-one Heavy atoms: 21 Torsion 5

Fig. 3(a-e): Derivatives of 4-benzylidene-amino-4,5 dihydro-2H 1,2,4 triazole-5 one

(Benzylidenamino) 4,5-dihydro-1H-1,2,4-triazole-5-one derivative has weak acidic properties. There is one weak acidic group N-CH3 and one ether group attached to benzene ring [42].

Virtual Screening of the Ligand library of 4-Benzylidene-Amino-4,5 Dihydro-2H 1,2,4 Triazole-5-one for Minimum energy calculation: After generation of ligand library docking was performed to get the lead molecule. It is known that if the free energy change of a chemical interaction is negative, the reaction will be feasible.

∆G = ∆H - T∆S.

Thus the molecule having minimum energy calculation has been selected as the lead compound. Docking score of different derivatives with enzyme cyp P450 present in various fungi has been calculated

Table No. 1: Docking score of “4-benzylidene-amino-4,5 dihydro- 2H 1,2,4 triazole-5” one with A.flavus.

Molecular Formula Mol Dock Score Re-rank Score H-Bond

C19H20N4O3 -78.5012 -64.2347 0 C20H22N4O3 -85.4775 -63.2268 0 C20H21N4O3 -94.0173 -65.384 -2.62131 C15H20N4O3 -72.4336 -60.1647 -2.14971 C14H18N4O3 -82.4286 -68.9746 -2.39419

1-methyl-3-chloro benzyl-4-(3-ethoxy-4-methoxybenzylidenamino)-4,5-dihydro-1H-1,2,4-triazole-5-one shows the minimum energy calculation (-94.0173) and maximum mol dock score was shown by 1-methyl-3-ethyl-4-(3-ethoxy-4-methoxybenzylidenamino)-4,5-dihydro-1H-1,2,4-triazole-5-one (-72.4336).



Fig. 4(a): Residue around the cavity with

which receptor binds

Fig. 4(b): Hydrogen bond interaction

between lead compound and Lys 38 and Tyr 42 residues

Fig. 4(c): Binding position of ligand at the

surface of receptor

Fig. 4(d): Binding of ligand at the cavity of

enzyme

Fig. 4(a-d): Interaction between top scorer derivative “1-methyl-3-chloro benzyl-4-(3-ethoxy-4-methoxybenzylidenamino)-4,5-dihydro-1H-1,2,4-triazole-5-one” with A.flavus

The results has been drawn in the fig. 6

Fig. 5: Comparative inhibitory effect of all the derivatives of 4 -benzylidene-amino-4,5 dihydro- 2H 1,2,4 triazole-5-one against A.flavu It has been observed that derivatives of “1-methyl-3-chloro benzyl-4-(3-ethoxy-4-methoxybenzylidenamino)-4,5-dihydro-1H-1,2,4-triazole-5-one” with chloro substituent shows the inhibitory effect and with methyl ethyl derivative shows the lowest inhibitory effect for A.flavus.

The results have been corrobora ted by the studies of Refat El Sayed in 2006, according to which derivatives with Chloro substituent behave as biologically active anionic surface active agents. QSAR studies governed by “Craig plot” with regard to the various substituents in a new drug molecule. The chloro group essentially enhance both electron withdrawing characteristics and hydrophobicity in the ‘drug like molecule’ by virtue of their σ +ve and π +ve effects.The results are also in confirmation with the findings of Altintas et al., in 2005 [1], according to which electron withdrawing hetero aromatic nucleus appreciably

acidified the remaining H-atom and increases drug potency, thus consistently improves antimi crobial activity.

Preclinical Pharmacology/Toxicology of Drug like Molecules (ADME/Tox Properties):

After selection of lead molecule preclinical pharmacology and toxicology study was carried out to find out the druglikeness of molecule. Factors such as a bsorption, distri bution, biotransformati on (metabolism) and elimination govern the ability of a drug to reach the active site soon after its administration [22]. Pharma algorithm is used to know the drug likeness of the lead molecule.

The summary of the ADME/Tox properties were mentioned in Table 2.

Table No. 2: ADME/Tox properties of “1-methyl-3-phenyl-4-(3-ethoxy-4-methoxybenz ylidenamino)-4,5-dihydro-1H-1,2,4 -triazole-5-one

Oral bioavailability more than 70%

Maximum passive absorption: 100% Contribution from: Trancellular route = 100% Paracellular route = 0% Permeability:Human Jejunum scale (pH=6.5): Pe, Jejunum = 4.95 x10-4 cm/s Caco-2 scale (pH=7.4, 500rpm): Pe, Caco-2 = 285.65 x10-6 cm/s Absorption rate: Ka = 0.099 min-1

Probability of Effect on

LD50 pLD50 Lower limit

Upper limit

Lower limit

Upper limit

Blood 0.61 Intra Peritoneal

550mg/kg -0.13 -0.90 0.49

Cardio-vascular system

0.54 Oral 710mg/kg -0.25 -1.74 0.03

Gastro-intestinal system

0.61 Intra Venous

66mg/kg 0.78 0.19 2.06

Kidney 0.37 Sub Cutaneous

400mg/kg 0.00 -1.49 1.16

Liver 0.21 Lung 0.25

SUMMARY AND CONCLUSION

The study was concerned with virtual screening of 1,2,4 triazole derivatives and their potential application on fungus A.flavus. The present work has been performed to get the effective drug like

molecule from the derivatives of 4-benzylidene-amino-4,5 dihydro- 2H 1,2,4 triazole-5-one through the chemoinformartics approach. The structure of drug like molecule was drawn and submitted by a server ie; CADD groups- chemoinformatics tools and users services option to



derive the pdb library of 1,2,4 triazole in mol 2 format. The sequence of amino acid in cyp P450 in Aspergillus flavus was retrieved from NCBI in fasta format. This sequence is then used to get the 3D structutre of cypP450 with the help of SWISS model. Drug target identification and docking of the ligand molecule with the protein was done with the help of MVD software. The triazole derivative with least negative docking score is supposed to be the most effective drug. The bioavailability, absorption, and toxicity of the drug like molecules were studied by pharma-algorithm. Absorption rate should be high, so that these molecules must be available for biological system. The results obtained demonstrate that the derivative with chloro substituent binds strongly with hydrophobic pocket and is effective antifungal agents against A.flavus.

Therefore, optimization of molecular structure with the help of homology based drug designing will lead to novel drug in future.

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Source of support: Nil, Conflict of interest: None Declared

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