Solutions For An Introduction to Medicinal Chemistry Chapter 17 Problem 10Q

Figure-1: The active structures of the eight structures, which are tested for agonist activity.

Since, the chosen biphenyl structure is not totally rigid, the bond rotation can happen. This results in different orientations of the aromatic rings, with respect to each other. Hence, the position of one phenyl ring can be replaced by a dummy atom or centroid to avoid the difficulty.

This position is best defined by the position of oxygen, which may act as both hydrogen bond donor as well as acceptor. Despite the bond rotation between the two aromatic rings, the position of centroid remains fixed and a pharmacophore can be defined consequently.

Figure-2: Depicts the bond rotations and definition of a pharmacophore.

Next, it is necessary to identify the active conformation for each of the structures before attempting an overlay of the structure with the biphenyl group. Conformational analysis now plays an important role for finding conformation(s) with previously identified pharmacophore. The common 2D (dimensional) pharmacophore of active molecules are depicted as colored whereas, dummy bonds are represented with dotted red lines as shown in the figure below.

Figure-3: shows the overlaid structures with the biphenyl group.

The identified relevant structures are overlaid with the biphenyl structure. The corresponding atoms, present in pairs in each structure, are matched by choosing

preferentially important atoms, such as, nitrogen, oxygen and centroid atoms, to the pharmacophore.