**Table 4.** *Calculated global descriptors of the selected NSAIDs were calculated using the DFT/B3LYP/6311G++(d,p) level*

 *of theory.*

#### *DFT and Molecular Docking Studies of a Set of Non-Steroidal Anti-Inflammatory Drugs … DOI: http://dx.doi.org/10.5772/intechopen.93828*

Hardness ð Þη

**Figure 3.**

*Density Functional Theory Calculations*

**78**

Electronegativity ð Þχ

Softness Sð Þ

Chemical potential ð Þ μ

Electrophilicity index ð Þ ω

According to the maximum hardness principle (MHP), at constant external potential, the stability of a molecule increases with hardness, and with the increase in stability, the reactivity decreases. Softness is just the reciprocal of hardness, so higher the softness, lower is the stability, *i.e*., higher is the reactivity. The hardness value of ketoprofen is 2.43; fenoprofen is 2.68, flurbiprofen is 2.60, and ibuprofen is 2.96. This study shows that ketoprofen has a lower hardness and a higher softness value which indicates that this drug is highly reactive compared to other drugs.

The calculated global descriptors of AMB are given in **Table 4.**

<sup>≈</sup> *IP*

*The MESP structures of (a) ketoprofen, (b) fenoprofen, (c) flurbiprofen and (d) ibuprofen. The negative (red) regions of MESP were related to electrophilic reactivity and the positive (blue) regions to nucleophilic reactivity.*

> ≈ 12*η*

� *EA*

≈ �

> ≈ *μ* 2 2 *η*

þ *EA*

<sup>≈</sup> *IP*

<sup>2</sup> (3)

<sup>2</sup> (4)

χ (6)

(5)

(7)

Ionization energy is a fundamental descriptor of the chemical reactivity of atoms and molecules. High ionization energy indicates high stability and chemical inertness, and small ionization energy indicates high reactivity of the atoms and molecules. If the electronic chemical potential is greater, then the compound is less stable or more reactive. Electron affinity refers to the capability of a ligand to accept precisely one electron from a donor. The electrophilicity index is described as a structural depictor for the analysis of the chemical reactivity of molecules. It measures the tendency of the species to accept electrons. A good, more reactive, nucleophile has a lower value of *ω*, in the opposite, a good electrophile has a high value of *ω*. Hence comparing the local descriptors of all selected drug we can infer that ketoprofen is more reactive with the lowest electrophilicity index and highest softness index and smallest hardness value. At the same time, the negative chemical potential of ketoprofen determines the stability of the drugs.

#### **3.5 Hyperpolarizabilities, polarisabilities and dipole moment**

The computational approach can also be used to study the interaction of electromagnetic fields in various media to produce new fields that are altered in frequency, phase and amplitude or other propagation characteristics from the incident fields. The polarization P, induced in a medium by an external electric field F is given by

$$\mathbf{P} = \mathbf{P}\_0 + \boldsymbol{\chi}^{(1)} \cdot \mathbf{F} + \boldsymbol{\chi}^{(2)} \cdot \mathbf{F}^2 + \boldsymbol{\chi}^{(3)} \cdot \mathbf{F}^3 + \dots \tag{8}$$

*βtotal* ¼

r

of 9*:*<sup>2128</sup> � <sup>10</sup>�<sup>31</sup> esu.

**3.6 Molecular docking**

*<sup>β</sup>xxx* <sup>þ</sup> *<sup>β</sup>xyy* <sup>þ</sup> *<sup>β</sup>xzz* � �<sup>2</sup>

*DOI: http://dx.doi.org/10.5772/intechopen.93828*

molecules to the appropriate target binding site.

*3.6.1 Molecular docking studies with COX-2*

**Samples Dipole moment**

**Table 5**.

**81**

*selected NSAIDs.*

**(μ) Debye**

Ketoprofen 3.20 �1*:*<sup>59</sup> � <sup>10</sup>�<sup>23</sup> <sup>9</sup>*:*<sup>21</sup> � <sup>10</sup>�<sup>31</sup> Ibuprofen 1.70 �1*:*<sup>35</sup> � <sup>10</sup>�<sup>23</sup> <sup>4</sup>*:*<sup>55</sup> � <sup>10</sup>�<sup>31</sup> Fenoprofen 1.16 �1*:*<sup>50</sup> � <sup>10</sup>�<sup>23</sup> <sup>5</sup>*:*<sup>17</sup> � <sup>10</sup>�<sup>31</sup> Flurbiprofen 2.68 �1*:*<sup>50</sup> � <sup>10</sup>�<sup>23</sup> <sup>3</sup>*:*<sup>95</sup> � <sup>10</sup>�<sup>31</sup>

*The calculated dipole moment μ (Debye), the polarizability β tot and first hyperpolarizability β tot of all*

ffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffi

The highest value of dipole moment is observed for ketoprofen, which is equal to

<sup>þ</sup> *<sup>β</sup>zzz* <sup>þ</sup> *<sup>β</sup>zxx* <sup>þ</sup> *<sup>β</sup>zyy* � �<sup>2</sup>

(12)

<sup>þ</sup> *<sup>β</sup>yyy* <sup>þ</sup> *<sup>β</sup>yzz* <sup>þ</sup> *<sup>β</sup>yxx* � �<sup>2</sup>

3.2078 Debye. The calculated average polarizability and first-order hyperpolarizability of the drug molecules are given in **Table 5**. All the samples exhibit better values compared to one of the prototypical molecules, Urea (μ and β of urea is 4.56 D and 4.8 � <sup>10</sup>�<sup>36</sup> esu respectively) [25]. Though all the molecules are NLO active molecule, ketoprofen has the highest among others with hyperpolarizability value

*DFT and Molecular Docking Studies of a Set of Non-Steroidal Anti-Inflammatory Drugs…*

Molecular docking is one of the most frequently used methods in structurebased drug design due to its ability to predict the binding conformation of small

1CX2 is an enzyme involved in arachidonic acid metabolism, where arachidonic acid is the precursor that is metabolized by various enzymes, especially cyclooxygenase-1 and -2 to a wide range of biologically and clinically important eicosanoids and metabolites of these eicosanoids. Two important pathways for arachidonic acid metabolism are the cyclooxygenase (COX) and 5-lipoxygenase (5-LO) pathways. The COX pathway forms intermediate compounds called cyclo-endoperoxides (PGG2 and PGH2). Enzymes, many of which are tissue specific, then convert the cycloendoperoxides into the final biologically active prostanoid. 1CX2 is a tetramer having four identical subunits and its chains C and D contain the inbuilt ligand SC-558 and the structure of the COX-2 enzyme is depicted in **Figure 4**. The amino acid residues in the active site of 1CX2 are TYR355, GLY354, SER353, LEU352, VAL349, TYR348, MET522, VAL523, GLY526, ALA527, SER530, LEU531, LEU359, ARG120, VAL116, HIS90, ARG513, ALA516, ILE517, PHE518, TRP387, TYR385, LEU384 and PHE381. **Figure 5(b)** demonstrates the 3-dimensional protein-ligand interaction SC-558 into the active site of 1CX2. The co-crystallized ligand SC-558 is found to be buried deep into the binding pocket of 1CX2. SC-558 interacts with the active site's amino acids of the protein by H-bonding with active site amino acids ARG513, SER353 and LEU352, which is well evidently observed from 2-D interaction picture as shown in **Figure 5(c)**. SC-558 interacts with COX-2 with a binding energy of �11.987 kcal/mol. After analyzing the protein-ligand interaction of 1CX2 with its co-crystallized ligand SC558, all the selected ligands ketoprofen, fenoprofen, flurbiprofen and ibuprofen were docked to the active site of 1CX2 and it is found that all the selected

**Polarizability (esu) Hyperpolarizability (esu)**

where χ(n) is the nth order susceptibility tensor of the bulk medium. The dipole moment of a molecule interacting with an electric field can be written

$$
\mu\_{\rm i} = \mu\_{\rm i}^{\rm 0} + \alpha\_{\rm i\bar{j}} \,\mathrm{F}\_{\rm j} + (\mathbf{1}/2) \mathfrak{f}\_{\rm i\bar{j}k} \,\mathrm{F}\_{\rm j} \,\mathrm{F}\_{\rm k} + (\mathbf{1}/6) \,\mathrm{Y}\_{\rm i\bar{j}k\bar{l}} \,\mathrm{F}\_{\rm j} \,\mathrm{F}\_{\rm k} \,\mathrm{F}\_{\rm l} + \tag{9}
$$

where μ<sup>i</sup> <sup>0</sup> is the permanent dipole moment and αij, βijk, ϒijkl is tensor elements of the linear polarizability and first and second hyperpolarizabilities respectively. This interaction may even lead to nonlinear optical effects (NLO). In this direction in order to study the NLO properties, the dipole moment, first static hyperpolarizability (βtot) and its related properties including α, β and Δα of all selected NSAIDs were calculated using DFT/B3LYP/6311G++(d,p) method based on the finite-field approach and are given in **Table 4**. The second-order term of the hyperpolarizability gives rise to sum and difference frequency mixing (including second harmonic generation) and optical rectification. The third-order term is responsible for the third-harmonic generation and two-photon resonances. The polarizability and hyperpolarizability of NLO can be written as tensors. While the linear polarizability tensor α as shown below which is a 3\*3 matrix having nine components as shown below.

$$\mathbf{a} = \begin{bmatrix} a\_{\mathbf{x}\mathbf{x}} & a\_{\mathbf{x}\mathbf{y}} & a\_{\mathbf{x}\mathbf{z}} \\ a\_{\mathbf{y}\mathbf{x}} & a\_{\mathbf{y}\mathbf{y}} & a\_{\mathbf{y}\mathbf{z}} \\ a\_{\mathbf{z}\mathbf{x}} & a\_{\mathbf{z}\mathbf{y}} & a\_{\mathbf{z}\mathbf{x}} \end{bmatrix} \tag{10}$$

$$a\_{total} = \frac{\left(a\_{\text{xx}} + a\_{\text{yy}} + a\_{\text{xx}}\right)}{3} \tag{11}$$

For the first hyperpolarizability, the quantity of interest β is a 3\*3\*3 matrix has *β xzz, β xxx, βxyy, βyyy, βyzz, βyxx, βzzz, βzxx βzyy, βxyz,* respectively, from which the x, y and z components of β are calculated as [12, 17–27]:

*DFT and Molecular Docking Studies of a Set of Non-Steroidal Anti-Inflammatory Drugs… DOI: http://dx.doi.org/10.5772/intechopen.93828*

$$\beta\_{\text{total}} = \sqrt{\left(\beta\_{\text{xxx}} + \beta\_{\text{xy}} + \beta\_{\text{xxx}}\right)^2 + \left(\beta\_{\text{yy}} + \beta\_{\text{yx}} + \beta\_{\text{yx}}\right)^2 + \left(\beta\_{\text{xxx}} + \beta\_{\text{xxx}} + \beta\_{\text{xy}}\right)^2} \tag{12}$$

The highest value of dipole moment is observed for ketoprofen, which is equal to 3.2078 Debye. The calculated average polarizability and first-order hyperpolarizability of the drug molecules are given in **Table 5**. All the samples exhibit better values compared to one of the prototypical molecules, Urea (μ and β of urea is 4.56 D and 4.8 � <sup>10</sup>�<sup>36</sup> esu respectively) [25]. Though all the molecules are NLO active molecule, ketoprofen has the highest among others with hyperpolarizability value of 9*:*<sup>2128</sup> � <sup>10</sup>�<sup>31</sup> esu.

#### **3.6 Molecular docking**

Ionization energy is a fundamental descriptor of the chemical reactivity of atoms and molecules. High ionization energy indicates high stability and chemical inertness, and small ionization energy indicates high reactivity of the atoms and molecules. If the electronic chemical potential is greater, then the compound is less stable or more reactive. Electron affinity refers to the capability of a ligand to accept precisely one electron from a donor. The electrophilicity index is described as a structural depictor for the analysis of the chemical reactivity of molecules. It measures the tendency of the species to accept electrons. A good, more reactive, nucleophile has a lower value of *ω*, in the opposite, a good electrophile has a high value of *ω*. Hence comparing the local descriptors of all selected drug we can infer that ketoprofen is more reactive with the lowest electrophilicity index and highest softness index and smallest hardness value. At the same time, the negative chemical

The computational approach can also be used to study the interaction of electromagnetic fields in various media to produce new fields that are altered in frequency, phase and amplitude or other propagation characteristics from the incident fields. The polarization P, induced in a medium by an external electric field F is

The dipole moment of a molecule interacting with an electric field can be written

the linear polarizability and first and second hyperpolarizabilities respectively. This interaction may even lead to nonlinear optical effects (NLO). In this direction in order to study the NLO properties, the dipole moment, first static hyperpolarizability (βtot) and its related properties including α, β and Δα of all selected NSAIDs were calculated using DFT/B3LYP/6311G++(d,p) method based on the finite-field approach and are given in **Table 4**. The second-order term of the hyperpolarizability gives rise to sum and difference frequency mixing (including second harmonic generation) and optical rectification. The third-order term is responsible for the third-harmonic generation and two-photon resonances. The polarizability and hyperpolarizability of NLO can be written as tensors. While the linear polarizability tensor α as shown below which is a 3\*3 matrix having nine

> *αxx αxy αxz αyx αyy αyz αzx αzy αzx*

� �

*<sup>α</sup>total* <sup>¼</sup> *<sup>α</sup>xx* <sup>þ</sup> *<sup>α</sup>yy* <sup>þ</sup> *<sup>α</sup>zz*

For the first hyperpolarizability, the quantity of interest β is a 3\*3\*3 matrix has *β xzz, β xxx, βxyy, βyyy, βyzz, βyxx, βzzz, βzxx βzyy, βxyz,* respectively, from which the x, y

3 7

<sup>5</sup> (10)

<sup>3</sup> (11)

where χ(n) is the nth order susceptibility tensor of the bulk medium.

α ¼

and z components of β are calculated as [12, 17–27]:

2 6 4

<sup>P</sup> <sup>¼</sup> P0 <sup>þ</sup> <sup>χ</sup>ð Þ<sup>1</sup> <sup>F</sup> <sup>þ</sup> <sup>χ</sup>ð Þ<sup>2</sup> F2 <sup>þ</sup> <sup>χ</sup>ð Þ<sup>3</sup> <sup>F</sup><sup>3</sup> <sup>þ</sup> … (8)

<sup>0</sup> <sup>þ</sup> <sup>α</sup>ij Fj <sup>þ</sup> ð Þ <sup>1</sup>*=*<sup>2</sup> <sup>β</sup>ijk Fj Fk <sup>þ</sup> ð Þ <sup>1</sup>*=*<sup>6</sup> <sup>ϒ</sup>ijkl Fj Fk Fl<sup>þ</sup> (9)

<sup>0</sup> is the permanent dipole moment and αij, βijk, ϒijkl is tensor elements of

potential of ketoprofen determines the stability of the drugs.

given by

where μ<sup>i</sup>

**80**

μ<sup>i</sup> ¼ μ<sup>i</sup>

*Density Functional Theory Calculations*

components as shown below.

**3.5 Hyperpolarizabilities, polarisabilities and dipole moment**

Molecular docking is one of the most frequently used methods in structurebased drug design due to its ability to predict the binding conformation of small molecules to the appropriate target binding site.

#### *3.6.1 Molecular docking studies with COX-2*

1CX2 is an enzyme involved in arachidonic acid metabolism, where arachidonic acid is the precursor that is metabolized by various enzymes, especially cyclooxygenase-1 and -2 to a wide range of biologically and clinically important eicosanoids and metabolites of these eicosanoids. Two important pathways for arachidonic acid metabolism are the cyclooxygenase (COX) and 5-lipoxygenase (5-LO) pathways. The COX pathway forms intermediate compounds called cyclo-endoperoxides (PGG2 and PGH2). Enzymes, many of which are tissue specific, then convert the cycloendoperoxides into the final biologically active prostanoid. 1CX2 is a tetramer having four identical subunits and its chains C and D contain the inbuilt ligand SC-558 and the structure of the COX-2 enzyme is depicted in **Figure 4**. The amino acid residues in the active site of 1CX2 are TYR355, GLY354, SER353, LEU352, VAL349, TYR348, MET522, VAL523, GLY526, ALA527, SER530, LEU531, LEU359, ARG120, VAL116, HIS90, ARG513, ALA516, ILE517, PHE518, TRP387, TYR385, LEU384 and PHE381.

**Figure 5(b)** demonstrates the 3-dimensional protein-ligand interaction SC-558 into the active site of 1CX2. The co-crystallized ligand SC-558 is found to be buried deep into the binding pocket of 1CX2. SC-558 interacts with the active site's amino acids of the protein by H-bonding with active site amino acids ARG513, SER353 and LEU352, which is well evidently observed from 2-D interaction picture as shown in **Figure 5(c)**. SC-558 interacts with COX-2 with a binding energy of �11.987 kcal/mol.

After analyzing the protein-ligand interaction of 1CX2 with its co-crystallized ligand SC558, all the selected ligands ketoprofen, fenoprofen, flurbiprofen and ibuprofen were docked to the active site of 1CX2 and it is found that all the selected


#### **Table 5**.

*The calculated dipole moment μ (Debye), the polarizability β tot and first hyperpolarizability β tot of all selected NSAIDs.*

**Figure 5.**

**Figure 6.**

**83**

*(d) ibuprofen into the active site of COX-2.*

*ibuprofen into the active site of COX-2.*

*DOI: http://dx.doi.org/10.5772/intechopen.93828*

*3-D protein-ligand interactions of the ligands (a) ketoprofen, (b) fenoprofen, (c) flurbiprofen and (d)*

*DFT and Molecular Docking Studies of a Set of Non-Steroidal Anti-Inflammatory Drugs…*

*2-D protein-ligand interactions of the ligands: (a) ketoprofen, (b) fenoprofen, (c) flurbiprofen and*

#### **Figure 4.**

*(a) Structure of the COX-2 enzyme having inbuilt ligand SC-558. (b) Protein-ligand interaction of SC-558 with 1CX2. (c) 2-D protein-ligand interaction of SC-558 with 1CX2.*

NSAIDs docked well deep into the binding pocket of 1CX2 with good gliding score, given in **Table 5**. **Figure 5** shows the 3-D protein-ligand interaction of all selected NSAIDs into the active site of COX-2.

Ketoprofen and fenoprofen were docked deeply into the active site region making interactions with the residues ARG120, TYR355, TYR385 and TRP387 while, flurbiprofen docked deeply into the active site region making interactions with the residues ARG120 and TYR355 and ibuprofen with residue TYR355 only (**Figure 6**).

### *3.6.2 Molecular docking studies with COX-1*

COX-1 is an enzyme that acts on arachidonic acid and produces housekeeping prostaglandins. It is a dimer having two identical structural units in which Chain B *DFT and Molecular Docking Studies of a Set of Non-Steroidal Anti-Inflammatory Drugs… DOI: http://dx.doi.org/10.5772/intechopen.93828*

*3-D protein-ligand interactions of the ligands (a) ketoprofen, (b) fenoprofen, (c) flurbiprofen and (d) ibuprofen into the active site of COX-2.*

**Figure 6.**

*2-D protein-ligand interactions of the ligands: (a) ketoprofen, (b) fenoprofen, (c) flurbiprofen and (d) ibuprofen into the active site of COX-2.*

NSAIDs docked well deep into the binding pocket of 1CX2 with good gliding score, given in **Table 5**. **Figure 5** shows the 3-D protein-ligand interaction of all selected

*(a) Structure of the COX-2 enzyme having inbuilt ligand SC-558. (b) Protein-ligand interaction of SC-558*

Ketoprofen and fenoprofen were docked deeply into the active site region making interactions with the residues ARG120, TYR355, TYR385 and TRP387 while, flurbiprofen docked deeply into the active site region making interactions with the residues ARG120 and TYR355 and ibuprofen with residue TYR355 only (**Figure 6**).

COX-1 is an enzyme that acts on arachidonic acid and produces housekeeping prostaglandins. It is a dimer having two identical structural units in which Chain B

NSAIDs into the active site of COX-2.

*Density Functional Theory Calculations*

*with 1CX2. (c) 2-D protein-ligand interaction of SC-558 with 1CX2.*

**Figure 4.**

**82**

*3.6.2 Molecular docking studies with COX-1*

and some nonstandard residues were deleted after the preprocessing and the structure of the protein are shown in **Figure 7**. The amino acid residues in the active site of 1EQG are TYR355, SER353, LEU352, VAL349, MET522, ILE523, ALA527, SER530, LEU531, LEU359, ARG120, VAL116, PHE518, GLY526, MET522, PHE518, TRP387, TYR385, LEU384 and PHE381.

All the selected ligands ketoprofen, fenoprofen, flurbiprofen, and ibuprofen were docked to the active site of COX-1 and it is found that all the selected NSAIDs docked well deep into the binding pocket of COX-1 with good gliding score, given in **Table 6** and binding energy were tabulated in **Table 7**. **Figure 8** shows the 3-D protein-ligand interaction of all selected NSAIDs into the active site of COX-1.

Ketoprofen and fenoprofen were docked deeply into the active site region making interactions with the residues TYR385, TRP387, ARG120 and TYR355 by forming two hydrogen bonds with ARG120 and TYR355, two pi-pi stacking

**Figure 8.**

**Figure 9.**

**85**

*(d) ibuprofen into the active site of COX-1.*

*into the active site of COX-1.*

*3-D protein-ligand interactions of the ligands (a) ketoprofen, (b) fenoprofen, (c) flurbiprofen, (d) ibuprofen*

*DFT and Molecular Docking Studies of a Set of Non-Steroidal Anti-Inflammatory Drugs…*

*DOI: http://dx.doi.org/10.5772/intechopen.93828*

*2-D protein-ligand interactions of the ligands (a) ketoprofen, (b) fenoprofen, (c) flurbiprofen and*

**Figure 7.** *Structure of COX-1.*


#### **Table 6.**

*The gliding score of all samples with COX-1 and COX-2 enzymes.*


#### **Table 7.**

*The binding energy of all samples with COX-1 and COX-2 enzymes.*

*DFT and Molecular Docking Studies of a Set of Non-Steroidal Anti-Inflammatory Drugs… DOI: http://dx.doi.org/10.5772/intechopen.93828*

**Figure 8.**

and some nonstandard residues were deleted after the preprocessing and the structure of the protein are shown in **Figure 7**. The amino acid residues in the active site

All the selected ligands ketoprofen, fenoprofen, flurbiprofen, and ibuprofen were docked to the active site of COX-1 and it is found that all the selected NSAIDs docked well deep into the binding pocket of COX-1 with good gliding score, given in **Table 6** and binding energy were tabulated in **Table 7**. **Figure 8** shows the 3-D protein-ligand interaction of all selected NSAIDs into the active site of COX-1. Ketoprofen and fenoprofen were docked deeply into the active site region making interactions with the residues TYR385, TRP387, ARG120 and TYR355 by forming two hydrogen bonds with ARG120 and TYR355, two pi-pi stacking

**Sample Gliding score with COX-2 Gliding score with COX-1**

**Sample Binding energy with COX-2 kcal/mol Binding energy with COX-1 kcal/mol**

Ketoprofen 9.280 11.242 Fenoprofen 8.694 10.863 Flurbiprofen 9.377 11.603 Ibuprofen 10.133 10.075

Ketoprofen 9.279 11.242 Fenoprofen 11.37 10.862 Flurbiprofen 9.377 11.602 Ibuprofen 7.468 10.075

*The gliding score of all samples with COX-1 and COX-2 enzymes.*

*The binding energy of all samples with COX-1 and COX-2 enzymes.*

of 1EQG are TYR355, SER353, LEU352, VAL349, MET522, ILE523, ALA527, SER530, LEU531, LEU359, ARG120, VAL116, PHE518, GLY526, MET522, PHE518,

TRP387, TYR385, LEU384 and PHE381.

*Density Functional Theory Calculations*

**Figure 7.** *Structure of COX-1.*

**Table 6.**

**Table 7.**

*3-D protein-ligand interactions of the ligands (a) ketoprofen, (b) fenoprofen, (c) flurbiprofen, (d) ibuprofen into the active site of COX-1.*

**Figure 9.**

*2-D protein-ligand interactions of the ligands (a) ketoprofen, (b) fenoprofen, (c) flurbiprofen and (d) ibuprofen into the active site of COX-1.*

interaction between phenyl ring of the ligand with amino acids TYR385 and TRP387 and one salt bridge with active site amino acids. Though the interactions are the same for ketoprofen and fenoprofen the binding energy is different, ketoprofen has a binding energy of 11.242 kcal/mol while that of fenoprofen is 10.863 kcal/mol. At the same time, flurbiprofen and ibuprofen docked deeply into the active site region making interactions with the residues ARG120 and TYR355 and ibuprofen with residue TYR355 only (**Figure 9**).
