PART 1:  THE ACTIVE CONFORMATION
 

Shown above is the two-dimensional structure of levothyroxine (T4).  Use this structure to orient yourself to the 3-D structure on the right.  Specifically find the ether oxygen, O[1], the two aromatic carbons C[2] and C[3], the four iodo groups numbered 9, 11, 17, and 19.  Note that the numbering here is different from that above.  This is unavoidable as the molecular modeling program assigns the numbers to the atoms according to its own convention.  This should not be problematic if you remember the following:  I[11] = 3-I            I[9] = 5-I  I[17] = 3'-I           I[19] = 5'-I The 3-D structure represents the active conformation of levothyroxine.  Using either the on-screen trackball function or the right and bottom rotation bars, rotate the molecule, viewing it from several different directions.  Note that in this active conformation, the two aromatic rings lie perpendicular to one another.

THE IMPORTANCE OF THE 3- AND 5-IODO GROUPS
There are several similarities between thyroid SAR and the SAR for 1,4-dihydropyridines (calcium channel blockers which will be discussed in PHBMS 424), and NSAIDs (discussed breifly in PHBMS 422).  For all three classes of compounds, any structural feature which serves to restrict rotation and "lock in" the active, perpendicular conformation will increase the ability of the compound to bind to its receptor.  For thyroid hormones, it is the 3- and 5-iodo groups which provide this function.  Iodine atoms are extremely large and bulky and when placed at positions 3 and 5 of the A ring, force the two aromatic rings to remain perpendicular.  Otherwise stated, they restrict rotation about the O[1]-C[2] and O[1]-C[3] bonds.  Let's examine this further.  In this exercise, you will toggle between "Ball and Stick" and "Space Filling" views.  The former view is best for selecting individual atoms and bonds, while the latter view provides a more acurate depiction of the size of the iodine atoms.

• Prior to proceeding, please refresh/reload this page.
• Click on the ether oxygen, O[1], to highlight it.  A white circle should appear around the atom.  Change the view to Space Filling mode.  This is the side view of the molecule.  Note the size of the iodine atoms (purple) relative to all of the other atoms.
• Using the bottom and right rotation bars, examine the molecule using the rear (i.e., the phenol containing aromatic ring) and overhead views.  These two views very nicely demonstrate the bulkiness of the iodine atoms and the perpendicular nature of the rings.
• Use the left rotation bar, rotate the O[1]-C[2] bond approximately 45 degrees in either direction.  Again view the molecule from the side, overhead and the rear.
• QUESTION 1:  Judging by what you see on the screen, is this rotation favorable or unfavorable?  Briefly explain your answer.
• Note:  there is nothing special about the 45 degree rotation.  You can repeat this process using larger or smaller rotations; however, your answer to the above question should not change.
• Optional:  It is also possible to rotate the bond between the ether oxygen, O[1], and the phenol containing aromatic ring.  To do this, first reload/refresh the page.  Next, select the O[1]-C[3] bond by clicking on it.  Both atoms should have a white ring around them if this is done properly.  Again, change to Space Filling mode, rotate the selected bond using the left rotation bar, and examine the molecule from the same perspectives as you did earlier.  Is this rotation favorable or unfavorable?  Why or why not?

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