Shown above is the two-dimensional structure of indomethacin.  Use this structure to orient yourself to the 3-D structure on the left.  Specifically, make sure that you find the pyrrole nitrogen, N[1], and the four carbons which are numbered 7, 10, 11, and 19.  These numbers correspond to the atom numbers in the 3-D model.  These atoms will be used to demonstrate the conformational restrictions present in the indomethacin molecule.

THE BINDING OF INDOMETHACIN TO THE NSAID RECEPTOR
Using either the on-screen trackball function or the right and bottom rotation bars, rotate the whole molecule so that you can see the perpendicular nature of the indole ring system and the chlorine-containing aromatic ring.  Having viewed the 3-D image above, you should be able to envision how indomethacin would fit into the receptor model shown below.

Now let's examine the structural features present in indomethacin which help it to assume the required active conformation.

• As shown in the receptor model, the lower, chlorine-containing phenyl ring must be under the indole ring system.  This conformation is present in the 3-D model; however, the bond between the N[1] pyrrole and the C[10] carbonyl carbon is flexible and can rotate out of the active conformation.  In theory, it could fully rotate 180 degrees from its current position.  This portion of the exercise will examine if this rotation is favorable.
• Before changing the conformation, view the 3-D model in Space Filling Mode.  Note the interaction between the C[7] hydrogen, identified as H[39], and the phenyl ring.  You should be able to clearly see the center of the phenyl ring, which indicates that H[39] does not sterically interfere with the phenyl ring.  When finished, switch back to the Ball and Stick Mode.
• Click on the bond between N[1] and C[10].  A white ring should appear around each atom.  Using the left rotation bar, rotate the bond 180 degrees.  On some computers, the degree of rotation will be monitored in the text bar above the structure.  If you don't have this feature, just do your best to approximate 180 degrees.  If your computer does have the rotation bar don't be concerned if you see a negative sign in the rotation.  This just indicates the direction of rotation (which is of no concern here).
• Again change the view to Space Filling Mode, and look at the interaction of the phenyl ring with H[38], a hydrogen attached to the C[11] methyl group.
• Question 1:  How does the interaction of H[38] with the phenyl ring compare to what you observed above with H[39]?  Note that you can use the left rotation bar to rotate the bond 180 degrees as many times as necessary to compare the interactions.
• Question 2: What conclusions can you make regarding the C[11] methyl group (i.e., does it hinder activity or aid in activity and why)?  .
• When you are finished with these questions, reload the page.

• Rotation of the C[10]-C[19] bond will cause the compound to lose its perpendicular conformation and thus will decrease activity.  Ortho substitutions on the phenyl ring, as seen in the example below, will sterically prevent this rotation.  Even though the phenyl ring of indomethacin does not contain any ortho substituents, rotation about this bond is unfavorable.  To demonstrate why, do the following:
• Click on the bond between C[10] and C[19].
• Change the view to Space Filling
• Using the bottom rotation bar, rotate 90 degrees about the y-axis such that the chloro group of the phenyl ring is facing towards you.
• Using the left rotation bar, slowly rotate the C[10]-C[19] bond.
• Question 3:  Based upon what you see, please explain why this rotation is unfavorable.  Include atom numbers for any interactions you observe.
• The conclusion which can be reached here is that the perpendicular conformation is actually the least sterically hindered conformation, even without ortho substituents!  Imagine then the advantage of "locking" in this active, perpendicular conformation with the addition of ortho-substituents!