INSILICO DRUG ACTIVITY OF N-OXIDES

VALLI G.¹*, LALITHISWARI T.², JOTHIMALAR S.³, RAJESWARI N.^4
1Department of chemistry, The Standard Fireworks Rajaratnam College for Women, Sivakasi, 626123, Virudhunagar District, Tamil Nadu State, India
²Department of chemistry, The Standard Fireworks Rajaratnam College for Women, Sivakasi, 626123, Virudhunagar District, Tamil Nadu State, India
³Department of chemistry, The Standard Fireworks Rajaratnam College for Women, Sivakasi, 626123, Virudhunagar District, Tamil Nadu State, India
⁴Department of chemistry, The Standard Fireworks Rajaratnam College for Women, Sivakasi, 626123, Virudhunagar District, Tamil Nadu State, India
* Corresponding Author : mrs.valliravichandran@gmail.com

Received : 10-08-2010     Accepted : 30-12-2010     Published : 21-06-2011
Volume : 3     Issue : 1       Pages : 118 - 134
Int J Bioinformatics Res 3.1 (2011):118-134
DOI : http://dx.doi.org/10.9735/0975-3087.3.1.118-134

Conflict of Interest : None declared

N-Oxides were found to have antimicrobial activity. In continuation of our work on synthesis, characterization and biological activities (in vitro method) of N-Oxides and knowing their biological activities against micro organisms, we have correlated the biological activity of these N-Oxides against the micro organisms like Staphylococcus aureus, Salmonella typhi “H”, Escherichia Coli, Pseudomonas aeruginosa, Klebsiella aerogenes, Enterobacteraerogenes, Citrobacter, Staphylococcus epidermidis, and Aeromonas hydrophila by Insilico method. The target molecules (microorganism) were taken from Protein data bank. Various soft wares were used to find out the drug likeness properties of these N-Oxides. Online software “Molinspiration” was used to calculate log P (ie) Hydrophobicity of a drug. ACD/ Chemsketch was used to draw the structures of N-Oxides. Hex 4.2, docking software was used to predict the drug activities of these N-Oxides. The drug activities were measured in terms of drug likeness property by recording the E-Total value and compared with the marketed standard drugs for the above micro organism infections. Standard drugs were taken from drug bank. As per the standard norms, it was observed that the compounds that have negative E-Total values could be used as a drug. We have selected Ceftazidime ,Cefepime and Ceftizoxime as standard drugs among the available drugs for these microorganism for correlating the drug activities of these N-Oxides. We observed that some of our N-Oxides were found to have higher drug activities compared to standard drugs.

N-Oxides, log P, Hex 4.2, ChemSketch.

N-Oxides, have been found extensive use in the field of organic synthesis [1] , Pharmaceuticals [2] and corrosion inhibition studies. N-Oxides were found to have antimicrobial [3] , insecticidal, miticidal, pesticidal and repellent activities. N-Oxides have received great attention during recent years, because of their utility as important intermediates in organic synthesis. Some N-Oxides have also been used as spin trapping reagents and are utilized in studies concerning detection of radical species. Our work on synthesis, characterization and antimicrobial activities N-Oxides by in vitro method revealed that these N-Oxides were found to have moderate activity. Hence we would like to correlate these activities using Insilico method.

We have drawn the structures of N- Oxides using Molinspiration, which is an Online chemdraw tool and calculated Hydrophobicity (log P value) of these molecules.

Hydrophobicity of a molecule is measured by its log P value, where P is known as Partition coefficient.
Hydrophobicity affects drug absorption, bioavailability, hydrophobic drug-receptor interactions, metabolism of molecules, as well as their toxicity. The Log P value of a compound, which is the log of its partition coefficient between n-octanol and water, [log ( [octanol] / [water] )] . It has been shown for compounds to have a reasonable probability of being well absorb, their log P value must not be greater than 5.0.

The structures of 115 N-Oxides of different categories (I to XII series) were drawn in Molinspiration and the calculated log P values were listed in [Table-1] . Log P values indicate the hydrophobicity of a drug. We observed that some of the N-Oxides were found to have negative and very low log P values (less than 5). Hence they may possess the drug activity. We have already reported the in vitro drug activity of these N-Oxides and observed that they were found to have moderate drug activities. Knowing the drug activity of these N-Oxides, we planned to compare their drug activities with the standard drugs available in the market against some microorganism by Insilco method.

ACD/ChemSketch is an integrated software package from Advanced Chemistry Development Inc. for drawing chemical structures, reactions, schematic diagrams and other chemistry – related reports and presentations. We have drawn 115 N-Oxide in ACD/ Chem Sketch. One example is given in the following figure [Fig-1] and saved in pdb file format.
The following three antibiotics were taken as the standard drugs from the drug bank.

Ceftazidime is a third-generation cephalosporin antibiotic. Like other thir d- generation cephalosporins, it has broad spectrum activity against Gram-positive and Gram-negative bacteria. Ceftazidime is usually reserved for the treatment of infections caused by Pseudomonas aeruginosa.

Cefepime has an extended spectrum of activity against Gram-positive and Gram-negative bacteria, with greater activity against both Gram-negative and Gram-positive organisms than third-generation agents. Cefepime has good activity against important pathogens including Pseudomonas aeruginosa, Staphylococcus aureus, and multiple drug resistant Streptococcus pneumoniae. A particular strength is its activity against Enterobacteriaceae.

Ceftizoxime is a third generation Cephalosporin antibiotic. It is used for the treatment of lower respiratory tract infections, Urinary tract infections caused by E.Coli, S.aureus, Enterobacter and Klebsiella species. It has higher activity against Aeromonas hydrophila. Ceftizoxime has cross sensitivity with penicillin allergies.

Macromolecular Docking was done using HEX 4.2 – software using Spherical Polar Fourier Correlations. In Hex's docking calculations, each molecule is modeled using 3D parametric functions, which are used to encode both surface shape and electrostatic charge and potential distributions. With suitable scaling factors, this docking score can be interpreted as interaction energy. Hex reads protein and DNA molecular structures from PDB- format files. These are treated as receptor.

In order to run a docking calculation in Hex, first we have to load a receptor and a ligand in pdb file format structure using the
File pull-down menu. Then Docking can be carried out using the options.
Controls → Docking → Activate.
To save the Docking Results:
The current docking orientation can be written to a single pdb
file by selecting
File → Save → Both.

Various steps involved are:
• Structure of the N-Oxides was drawn using the drawing tools in ACD/ChemSketch as given in [Fig-1] .
• The 3D structure of the receptors (Microorganisms) were obtained from Protein Data Bank.
• Docking menu was clicked to carryout Docking process.
The result obtained after docking gets completed were shown in [Fig-2] as examples.
We have calculated the E-Total value of N-Oxides against Staphylococcus aureus, Escherichia coli, Pseudomonas aeruginosa, Enterobacter aerogenes, Citrobacter, Staphylococcus epidermidis, Aeromonas hydrophila, Salmonella typhi “H” and Klebsiella Aerogenes micro-organisms using Hex 4.2 docking software, and observed that some of our N-Oxides have been found to have higher drug activities than the standard drugs.

All the 115 N-Oxides were made to undergo docking with the selected microorganism and their E-Total were recorded. Some of the N-Oxides were found to possess higher drug activities than the standard and are tabulated as given below with respect to the selected microorganisms.

Among the 115 N-Oxides, XII i (-246.60), XII d (-241.38), XII g (-238.18), XII f (-237.02), XII c (-236.36), XII j (-236.35), XII h (-230.43) were found to have higher value than Cefepime. [Table-2]

Twenty one N-Oxides were found to have higher activities than Ceftizoxime against Staphylococcus aureus. [Fig-3] & [Table-3]

A. Compared to standard Ceftazidime, compound XII i was found to possess higher drug activity with the energy value -262.17. The standard drug value is -242.45.
B. Comparison with Cefepime:
Compared to Cefepime ten N-Oxides as mentioned in [Table-4] have higher drug activities against Salmonelle typhi “H”
C. Comparison with Ceftizoxime:
XII i, VI g, XII h, XII f, XII j, XII g, XII e and VII i N-Oxides were observed to have higher drug activity than Ceftizoxime [Table-5] .

A. Comparison with Cefepime:
Seven N-Oxides (listed in Table-VI) were shown higher drug activities than Cefepime.
B. Correlation with Ceftizoxime:
Thirty seven N-Oxides were observed to have higher drug activity than Ceftizoxime [Table-7] .

A. Comparison with Ceftazidime:
Compounds XII i (-246.32), XII d (-235.14) and XII g (-235.14) were shown higher activities than Ceftazidime(-234.36).
B. Correlation with Cefepime:
Compounds XII i (-246.32), XII d (-235.14), XII g (-235.14) and XII f (-230.54) possessed higher activities than Cefepime(-230.48).
C. Comparison with Ceftizoxime:
Compared to the standard Ceftizoxime, XII i, XII d, XII g, XII f, XI e, XII j, XII h, XII c, VI i, III i, XII b, XII e, VII i, and XII a were having higher activities against Pseudomonas Aeruginosa [Table-8] .

A. Comparison with Ceftazidime:
Forty two compounds were found to have higher drug activities. Among these N-Oxides compound VIg possessed greater activity than standard Ceftazidime. [Table-9] .
B. Comparison with Ceftizoxime:
Compared to standard Ceftizoxime, compound VI g was found to possess higher drug activity against Klebsiella Aerogenes with the energy value -213.39 which was greater than the standard drug value, -208.84.

A. Comparison with Ceftazidime:
The E-total value of Compounds XII c (-200.18), XII b (-198.91), XII i (-197.09),
XII d (-195.20), VI i (-190.19) and Ceftazidime (-185.85) were observed.
B. Comparison with Ceftizoxime:
Compared to Ceftizoxime (-196.73) Compounds XII c (-200.18), XII b (-198.91), XII i (-197.09) were found to possess higher drug activities.

A. Correlation with Ceftazidime and Ceftizoxime:
E-Total for Compounds and the standard were VI i (-210.56), VI g (-204.72), XII a (-204.52) Ceftazidime (-202.49) and Ceftizoxime(-201.84).

A. Correlation with Ceftazidime:
Twenty one N-Oxides were found to have higher drug activities. Among these compounds VI i have higher drug activity than the standard Ceftazidime against Staphylococcus Epidermidis. [Table-10]
B. Comparison with Ceftizoxime:
Drug activities of Compounds XII f (-205.44), VI i (-204.36), XII a (-200.08) were higher than Ceftizoxime (-195.89).

A. Comparison with Ceftazidime:
Among the thirty nine N-Oxides given in [Table-11] , the compound XII c (2 - {(Z) - [ (4-hydroxyphenyl) (oxido) - λ⁵- azanylidene ] methyl} phenyl 4-methylbenzene sulfonate) was found to possess higher drug activity than the standard Ceftazidime against Aeromonas Hydrophila.
B. Comparison with Cefepime:
From the result given in [Table-12] , Compound XII c (2-{(Z)- [ (4-hydroxyphenyl)(oxido)-λ⁵-azanylidene]methyl} phenyl 4-methylbenzenesulfonate) showed higher drug activity than the standard Cefepime against Aeromonas Hydrophila.
C. Comparison with Ceftizoxime:
Compounds XII c (-161.75), and XII b (-160.97) were having higher drug activities than the standard Ceftizoxime (-154.55).

Insilico drug activity comparison revealed the following observations:
• The compound XII i was found to possess higher drug activity against Staphylococcus aureus, Salmonella typhi “H”, Escherichia Coli and Pseudomonas Aeruginosa.
• The compound VIg possessed greater drug activity against Klebsiella Aerogenes.
• The compound XIIc have shown higher drug activity against Enterobacter Aerogenes.
• The compound Vii showed higher drug activity against Citrobacter and Staphylococcus Epidermidis.
• The compound XIIc observed to have higher drug activity against Aeromonas Hydrophila
than the standard drugs chosen for the comparison of drug activities
We observed that the antimicrobial activity determination by both Invitro and Insilco methods are parallel in their result and revealed that these N-Oxides can be used as an antimicrobial agent.

[1] Valli G., Muthusubramanian S. and Sivasubramanian S. (1998) Indian Journal of Heterocycles, 8, 153-154.  
» CrossRef   » Google Scholar   » PubMed   » DOAJ   » CAS   » Scopus  

[2] Valli G., Sivakolunthu S., Muthusubramanian S. and Sivasubramanian S. (2000) J.Indian Chem.Soc. 77, 252-253.  
» CrossRef   » Google Scholar   » PubMed   » DOAJ   » CAS   » Scopus  

[3] Valli G., Sivakolunthu S., Muthusubramanian S. and Sivasubramanian S. (2002) J. Indian Chem.Soc. 79, 79-80.  
» CrossRef   » Google Scholar   » PubMed   » DOAJ   » CAS   » Scopus  

[4] Ryan K.J., Ray C.G. (editors) (2004) Sherris Medical Microbiology (4th ed.). McGraw Hill. ISBN 0-8385-8529-9.  
» CrossRef   » Google Scholar   » PubMed   » DOAJ   » CAS   » Scopus  

[5] Whitt Dixie D., Salyers Abigail A. "14". Bacterial Pathogenesis: A Molecular Approach (2nd edition ed.). USA: ASM Press. ISBN 1- 55581-171-X.  
» CrossRef   » Google Scholar   » PubMed   » DOAJ   » CAS   » Scopus  

[6] Kitchen D.B., Decornez H., Furr J.R., Bajorath J. (2004) Nature reviews. Drug discovery 3 (11) 935-49.  
» CrossRef   » Google Scholar   » PubMed   » DOAJ   » CAS   » Scopus  

[7] Jorgensen W.L. (1991) Science 254 (5034): 954-5.  
» CrossRef   » Google Scholar   » PubMed   » DOAJ   » CAS   » Scopus  

	Fig. 1-
	Fig. 2- Against Staphylococcus aureus
	Fig. 3-
	Table 1-
	Table 2- Against Staphylococcus aureus
	Table 3- Against Staphylococcus aureus
	Table 4- Against Salmonelle typhi “H”
	Table 5- Against Salmonelle typhi “H”
	Table 6- Against Escherichia Coli
	Table 7- Against Escherichia Coli
	Table 8- Against Pseudomonas Aeruginosa
	Table 9- Against Klebsiella Aerogenes
	Table 10- Against Staphylococcus Epidermidis
	Table 11- Against Aeromonas Hydrophila
	Table 12- Against Aeromonas Hydrophila