DavidsonX – D001x – Medicinal Chemistry
Chapter 9 – Binding, Structure, and Diversity
Part 3 – Drug-Target Complementarity
Video Clip – Pharmacophores Revisited
Intermolecular forces hold a drug to its target. The intermolecular forces will not form,
however, unless the drug's functional groups are oriented to interact strongly the the
functional groups in the target. In other words, a drug needs the right functional groups with
the correct geometry in order to bind strongly to a given target. Proper functionality and
geometry describe a drug's pharmacophore.
The idea of pharmacophores were introduced back in Chapter 1. The pharmacophore of
morphine and the sulfa drugs were discussed in terms of very molecular scaffolds.
(1) benzene ring
(3) two carbon linker
morphine
pharmacophore
O O
S
R
N
H
H2N
N
(4) tertiary amine
(2) quaternary carbon
sulfonamide
antibiotic
pharmacophore
R = H, acyl, aryl, heteroaryl
Pharmacophores are more often described in terms of functional groups and their ideal
spacing. A hypothetical example is shown below. The pharmacophore consists of a
hydrogen bond donor, a negatively charged group, and a large non-polar group each
separated by a certain distance.
non-polar
group
hydrogen
bond
donor
negatively
charged
group
To satisfy these functional groups, one might select an alcohol (hydrogen bond donor),
carboxylate (negatively charged group), and a phenyl ring (non-polar group). Furthermore,
these might be connected as shown in compound 1 to give the appropriate spacing.
H
alcohol
O
H
O
phenyl
O
O
carboxylate
O
molecule
satisfying
pharmacophore
1
O
A problem with structure 1 is its conformational flexibility. While the structure is drawn to
show an ideal orientation of the key functional groups, the molecule has a huge number of
conformations that would improperly space the functionality. Indeed, some medicinal
chemists recommend downgrading hits that have a high number of freely rotating bonds.
The most common method for restricting flexibility of a molecule is the incorporation of rings
or double bonds. Several possible restricted structures are shown below. Compounds 2
through 4 incorporate alkenes. Alkenes restrict conformations somewhat. Compounds 4
through 7 incorporate rings at different positions. Rings can greatly restrict flexibility and hold
functional groups in a desired relative orientation. A problem with introducing rings is that
they normally add extra carbons to the molecule. New carbon might add steric bulk to the
structure and prevent binding.
H
O
H
O
2
H
O
4
O
O
6
O
O
H
O
O
H
O
H
O
3
7
5
O
O
O
O
O
O
O
Pharmacophores often include many key functional groups, certainly more than just three.
With four functional groups, unless they happen to lie within a plane, the pharmacophore will
occupy a three-dimensional space. With three-dimensional space comes the importance of
stereochemistry. While many drugs do not contain stereocenters, some do. Those that do
contain stereocenters are often approved exclusively in a single enantiomer form. In these
cases, the correct stereochemical configuration is normally required to achieve proper threedimensional orientation of the drugs functional groups for proper activity. Two examples of
drugs that are marketed as single enantiomers are naproxen (8) and duloxetine (9).
CH3
S
CO2H
O
CH3O
naproxen
(Aleve)
analgesic
8
duloxetine
(Cymbalta)
antidepressant
N
H
CH3
9