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ORIGINAL ARTICLE
Year : 2012  |  Volume : 2  |  Issue : 2  |  Page : 156-162

Molecular modifications of ibuprofen using Insilico modeling system


Pharmacy Department, Oman Medical College, Muscat, Oman

Date of Submission25-Jul-2011
Date of Acceptance20-Sep-2011
Date of Web Publication9-May-2012

Correspondence Address:
A R Mullaicharam
Pharmacy Department, Oman Medical College, Muscat
Oman
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/2231-0738.95991

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   Abstract 

Aim: The aim of our study was to develop new ibuprofen, that is better effect and less side effect using computer aided drug design. We found totally 10 molecular modifications of ibuprofen. Accordingly structure 9 is considered as the most appropriately modified ibuprofen drug that would have significant effect than the parent ibuprofen. Objective: To study Insilico molecular modifications of ibuprofen with physiochemical properties and drug likeness parameters to develop better drug with less side effect. Materials and Method: Molinspiration and Chemsketch are the two types of softwares used to perform the molecular modelings. Result: The Structure 9 is a best candidate among 10 structures, because it is similar to acelofenac, derivative of diclofenac which is already available in the market. Detailed molecular modeling using Dockin studies and toxicities studies can be carried out before synthesis of these derivatives.

Keywords: Chemsketch, ibuprofen, drug design, molecular modification


How to cite this article:
Halligudi N, Mullaicharam A R, Al-bahri H. Molecular modifications of ibuprofen using Insilico modeling system. Int J Nutr Pharmacol Neurol Dis 2012;2:156-62

How to cite this URL:
Halligudi N, Mullaicharam A R, Al-bahri H. Molecular modifications of ibuprofen using Insilico modeling system. Int J Nutr Pharmacol Neurol Dis [serial online] 2012 [cited 2019 Sep 21];2:156-62. Available from: http://www.ijnpnd.com/text.asp?2012/2/2/156/95991


   Introduction Top


Molecular modification is chemical alteration of a known and previously characterized lead compound for the purpose of enhancing its usefulness as a drug. This could mean enhancing its specificity for a particular body target site, increasing its potency, improving its rate and extent of absorption, modifying to advantage its time course in the body, reducing its toxicity, changing its physical or chemical properties (like solubility) to provide desired features.

Molecular modification is used to enhance drug's water solubility by incorporating water solubilizing groups in its structure. [1]


   Modeling Software for Molecular Mechanics Top


  • VMD- Visual Molecular Dynamics
  • MOLDY - Free MD program
  • GROMACS Molecular Dynamics on Parallel Computers
  • GROMOS Dynamic Modelling of Molecular Systems
  • MSI/Biosym Molecular Modelling Software
  • NAMD - Scalable Molecular Dynamics
  • PMD- Parallel Molecular Dynamics which is also archived at CCL
  • TINKER package for molecular mechanics and dynamics

   Intermolecular Interactions and Docking Top


  • AutoDock
  • DOCK "docking" molecules
  • FlexXautomatic prediction of receptor-ligand interactions
  • HYDRO calculation of hydrodynamic properties
  • LIGPLOT Program for automatically plotting protein-ligand interactions
  • SPROUT de novo ligand design
  • STALK: A Molecular Docking System
Molinspiration

Molinspiration is an independent research organization based on development and application of modern cheminformatics techniques, particularly in connection with the Internet.

Calculation of molecular physicochemical properties relevant to drug design and QSAR, including logP, molecular polar, surface area (PSA), and the Lipinski'sRule [2] of 5 descriptors. Calculation of activity score and drug-likeness for GPCR ligands, ion channel modulators, kinase inhibitors and nuclear receptor ligand(interactive virtual screening), choose the "Predict Bioactivity" option. [3] Molinspiration supports also internet chemistry community by offering free on-line Cheminformatics services for calculation of important molecular properties (for example log P, polar surface area, number of hydrogen bond donors and acceptors), as well as prediction of bioactivity score for the most important drug targets (GPCR ligands, kinase inhibitors, ion channel modulators, nuclear receptors) and possible molecular toxicity.

Hundreds of user's mol inspiration software is used in industry and academia to produce high-quality cheminformatics science. [3]

Chemsketch

A commonly used chemical drawing program for 2D and 3D structures, copyright of Advanced Chemistry Development, Inc. The program has certain additional features including calculation of molecular weight, calculation of percentages of elements present, IUPAC name generation, and viewing in RasMol

The commercial version of ACD/ChemSketch offers additional capabilities above and beyond the freeware offering. It includes a number of advanced features including a dictionary of more than 165,000 trivial, common, and trade names with their corresponding structures. It allows the user to view SDfiles, and search Microsoft Word or Adobe PDF reports, SDfiles, mol files, and Cambridge Soft ChemDraw files by chemical structure, substructure, or structure similarity. [4]

Lipinski's Rule of Five is a rule of thumb to evaluate drug likeness, or determine if a chemical compound with a certain pharmacological or biological activity has properties that would make it a likely orally active drug in humans. The rule was formulated by Christopher A. Lipinski in 1997, based on the observation that most medication drugs are relatively small and lipophilicmolecules.

Lipinski's rule says that, in general, an orally active drug has no more than one violation of the following criteria:

  • Not more than 5 hydrogen bond donors (nitrogen or oxygenatoms with one or more hydrogenatoms)
  • Not more than 10 hydrogen bond acceptors (nitrogen or oxygenatoms)
  • A molecular weight under 500 daltons
  • An octanol-water partition coefficient log P of less than 5
  • The guidelines predict that poor absorption or permeation of an orally administered compound is more likely if the compound meets the following criteria:
  • Molecular mass greater than 500 Da
  • High lipophilicity (expressed as cLogP greater than 5)
  • More than 5 hydrogen bond donors
  • More than 10 hydrogen bond acceptors [3]
The diversity of possible drug targets (of which each requires a different combination of matching molecular characteristics) is so enormous, that we do not believe that it is possible to find a common denominator for all of them and to express molecule drug-likeness by a single magic number. Simple count criteria (for example limits for molecular weight, log P, or number of hydrogen bond donors or acceptors) have also relatively limited applicability and are useful only to discard obvious non-drugs. [5]

Ibuprofenprofile

Ibuprofen is only very slightly soluble in water. Less than 1 mg of ibuprofen dissolves in 1 ml water (< 1 mg/mL). However, it is much more soluble in alcohol/water mixtures [Scheme 1]. [ 6]



The candidate drug of ibuprofen



Physical properties

Physical state: White crystalline powder,

Melting point" 75-78° c,

Solubility in water: Practically insoluble

Stable under ordinary conditions [7]

The aim of our study was to develop new ibuprofen, that have better effect and with less side effectsby using computer aided drug design [Scheme 2]. Accordingly structure 9 [Table 1] is consider as the most approperiatelymodifiedibuprofen drug that would have significant effect than the parent ibuprofen
Table 1: Chemical modification of ibuprofen

Click here to view


Materials

Ibuprofen pure drug. (National Pharmaceutical Industry, Muscat.)

Soft Wares:

Mol inspiration

Chemketch

Methods

Steps used for Molinspiration

Two methods were used to calculate the properties and to predict bioactivity of given molecule:

  1. Given molecule was drawn and press the [Calculate Properties] or [Predict Bioactivity] button. When the JME input is not working on your computer, try our NEW WebME Ajax editor NEW or paste raw SMILES here. You may wish to check also our Property Prediction FAQ or more information about calculated properties and drug likeness.
  2. When the graphical structure input is not available, Input given molecule as a SMILES string and press the [Calculate Properties] or [Predict Bioactivity] button.
Methods of using chemsketch

Upon startup, the Draw Normalmode and Carbonare automatically selected. By clicking and dragging the cursor in the window, C-C bonds are created. Clicking on a carbon atom produces a branched structure, e.g., isopropyl. The software keeps track of the valency of the atoms and alerts you if this is exceeded by crossing out the atom. By repeatedly clicking on a bond, the saturation will cycle from single bond to double bond to triple bond. If you have made an error in drawing, click Eraseand click on the atom to remove it.

After drawing the desired structure, option tool was clicked and then clean structure was chosen to modify the drawing structure.

Then, the same bottoms was again used to get the name of the structure by select the generate option.

After that, the same bottoms was used to get the all properties of the structure by chosen calculate all the properties and a table of all properties will appear. [Table 2] includes some properties such as: Parachor, surface tension, molecular weight, molecular formula, density, refractive index, and molar volume.
Table 2: Physicochemical properties of chemical modifications of ibuprofen

Click here to view


Smile notation

SMILES as a simple yet comprehensive chemical language in which molecules and reactions can be specified using ASCII characters representing atom and bond symbols. SMILES contains the same information as is found in an extended connection table but with several advantages. A SMILES string is human understandable, very compact, and if canonicalized represents a unique string that can be used as a universal identifier for a specific chemical structure. In addition, a chemically correct and comprehensible depiction can be made from any SMILES string symbolizing either a molecule or reaction.

SMILES development was initiated by David Weininger in the late 1980s using the concept of a graph with nodes as atoms and edges as bonds to represent a molecule. Parentheses are used to indicate branching points and numeric labels designate ring connection points. The basic SMILES grammar also includes as well as isotopic information, configuration about double bonds, and chirality leading to what is known as isomeric SMILES.



The smile notation helps in determine the more appropriate structure that has the same efficacy of ibuprofen this because the smile notation will determine some important properties for example: Kinase values that play significant rule as it has anti -inflammatory effect in which is needed to maintain an effective drug similar to ibuprofen [Scheme 3].

Also, smile notation provides a table of lipinski properties (e.g.: Molecular weight, hydrogen acceptor and donation, log P values and lipophilicity). The more similar or close of those values to the ibuprofen, the more effective and acceptor is the selected structure. [8]

By using two important softwares we obtain the following 10 modified structures


   Result and Discussion Top


To perform this study software programs like mol inspiration was used because it is freely available, easy to accessibility and it gives 2D and 3D of the structure. Also, it gives the physiochemical properties of the structure for example: Parachor, refractive index, surface tension, molar volume. Furthermore, it provide a table of values lipiski properties such as molecular weight, hydrogen acceptor and donation, log P values Graph 1 and lipophilicity thus it is easy to determine which structure is within the range of lipinski rules of 5 as it, says that, in general, an orally active drug has no more than one violation of the following criteria:

  • Not more than 5 hydrogen bond donors (nitrogen or oxygenatoms with one or more hydrogenatoms)
  • Not more than 10 hydrogen bond acceptors (nitrogen or oxygenatoms)
  • A molecular weight under 500 daltons
  • An octanol-water partition coefficient log P of less than 5 [9]




As result any drug structures not obey to the lipinsk's rules of 5 will not have any therapeutic activities. Drug likeness is also provided by molinspiration. It is very important that new structurehave similar properties as the original structure of ibuprofen; having the same pharmcokinetic and same pharmacodynamic properties.

The results mentioned in the above [Table 2] the table indicate that most of the structures have shown increasing in their log P values, although the log P values increased as the number of carbon increase; structure 5 has decreased in its log P. This is due to the place where the modification locates. Log P values decreased in Structure 6 and 7 [Graph 2] because of basic group (amide group) that decrease the lipophilisity and thus log P value decreased. Structure 9 has decreased it log P related to its polar group that decreases lipophilisty make compound more basic and less acidic. Although both structures 10 and 11 have electronegative group, structure 11 with Chloro group has decreased log P values because Chloro group is more electronegative and more polar than Fluor group.



Molar refractivity is a measure of the total polarizability of a mole of a substance and is dependent on the temperature, the index of refraction, and the pressure. while the molar refractivity increase, the refractive index (index of refraction) is a ratio of the speed of light in a vacuum relative to that speed through a given medium this quantity does not refer to an angle of refraction, which can be derived from the refractive index using Snell's Law). The above values conclude that molar refractivity is directly proportional with the log P value [Table 2].

Polarizability is an important fundamental property of subatomic particles. Polarizability determines the dynamical response of a bound system to external perturbations, and provides insight into the internal strong interaction structure. When the structures have more polar groups it become acidic in nature and it easily ionized (hydrophilic). The polarizability of the first four structures has increased because the log P also increased. [[Table 2], Graph 3] Thus, polarizability increased proportionally with the log P values. Structure 9 has the highest polarizability because of the polar group. Structure 10 has higher polarizability than structure 11 this due to fluro group that is more electro negative than chloro group, in structure 11 that make ionized easily.



Molecular weight is just the total weight of all the polymer molecules in a sample, divided by the total number of polymer molecules in a sample. All the structures are within the limit of lipinski rules that is molecular weight is less than 500Da, thus they are more lipophilic and easily cross the cell membranes and metabolize. For first 3 structures [Table 3] as the number of carbon increases the molecular weight also increases. And for remaining structures it varies depending on the respective change in functional group.
Table 3: Lipinski rule of 5 of chemical modifications of ibuprofen

Click here to view


All the structures obey Lipiski rules of Hydrogen acceptor and donation. L ipinski rules states that not more than 5 hydrogen bond donors (nitrogen or oxygenatoms with one or more hydrogenatoms) and Not more than 10 hydrogen bond acceptors (nitrogen or oxygenatoms). The values of hydrogen acceptor and donation important because it indicate wither the proposed drug is reversible or not and thus it can be predict the efficacy of the drug. For example, more than 5 hydrogen acceptor means the hydrogen bond are reversible that is needed in anti inflammatory drugs. Otherwise it might be irreversible and it effect May last more that may cause some problems in neurons sensation. Structure 9 has [Table 3] higher hydrogen donation than others this is because of the presence of the respective functional groups like CH 2 CH 2 COO H . .

As all the proposed structures have nil violations which mean that they are free from toxicity and have better pharmacokinetic and pharmacodynamic effect. It also predicts that there is a chance to develop new anti inflammatory derivatives drug that have better effect and less side effect than the parent ibuprofen.

Kinase value was chosen among many properties for our study, because it is related to the anti -inflammatory effect. Comparing to the original drug of ibuprofen, all other proposed structures are within the limit of ibuprofen except structure 6.

The more polar groups the more active is the structure. Therefore, structure 9 [Table 4] has shown the strongest anti inflammatory effects while structure 4 has lowest anti inflammatory effect. The electro negative group in structure 10 and 11 are more polar and its kinase values increased to -0.69 and -0.68respectively.[Table 3] shows direct relation between kinase values and log P values [Graph 4]. As log P increases the kinase value also increases. As log P increase the extent of ionization also increases. Accordingly the compound will be more lipophilic and it can cross the cell membrane.
Table 4: Anti inflammatory effect of compunds

Click here to view





   Conclusion Top


The aim of our study was to develop newderivative of ibuprofen, that have better effect and with less side effectsby using computer aided drug design. Accordingly structure 9 [Table 1] is consider as the most approperiatelymodifiedibuprofen drug that would have significant effect than the parent ibuprofen.it's log P is close to that of ibuprofen and it has the highest molecular refractivityand polarizability.Furthermore, it obey Lipinski Rules and has highest kinase values. This molecule would be having better pharmakokinetic and pharmocodinamic values.

Based on the physico chemical properties,structure 9as a best candiate among 10 structures, becauseit is similar to aceclofenac, derivative of diclofenac which is already available in the market.Detailed molecular modeling using Dockin studies and toxicities studies can be carried out before synthesis of this derivities.

Esters of ibuprofen using ethanol, propanol and butanol were prepared by using standard procedure and charectrize using melting point [Scheme 4].



 
   References Top

1.Available from: http://en.wikipedia.org/wiki/Molecular_modification. [Last accessed on 2011 July 10].  Back to cited text no. 1
    
2.Lipinski CA, Lombardo F, Dominy BW, Feeney PJ.Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings. Adv Drug Del Rev2001; 46:3-26.  Back to cited text no. 2
    
3.Uetrecht J. Prediction of a new drug's potential to cause idiosyncratic reactions. CurrOpin Drug DiscDevel2001; 4:55-9.  Back to cited text no. 3
    
4.Available from: http://www.medicinenet.com/nonsteroidal_antiinflammatory_drugs/article.htm. [Last accessed on 2011 July 10].  Back to cited text no. 4
    
5.Available from:http://www.molinspiration.com/docu/miscreen/druglikeness.html. [Last accessed on 2011 July 10].  Back to cited text no. 5
    
6.Available from:http://www.3dchem.com/molecules.asp?ID=14. [Last accessed on 2011 July 10].  Back to cited text no. 6
    
7.Available from:http://chemicalland21.com/lifescience/phar/ibuprofen.htm. [Last accessed on 2011 July 10].  Back to cited text no. 7
    
8.Weininger D. "SMILES, a chemical language and information system. 1. Introduction to methodology and encoding rules". JChemInfModel1988;28:31.   Back to cited text no. 8
    
9.Available from:http://www.bioscreening.com/reference/lipinski_rule.htm. [Last accessed on 2011 July 10].  Back to cited text no. 9
    



 
 
    Tables

  [Table 1], [Table 2], [Table 3], [Table 4]


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