University
UniversityofofJordan
Jordan
Faculty
FacultyofofPharmacy
Pharmacy
NOTES
www.iSpatula.com
Pharma2012
Summer semester
Medicinal
Chemistry 1
Price:______________
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L09
L09.Medicinal Ch. 05.07.2015
Husam A. Salamat
Structure-Receptor binding relationship, continued...
Last lecture we've been discussing how the factors influencing topological fit are related
to biological activity; we'll continue our discussion about conformational isomerism.
Rotable bond is a single bond connecting two atoms that are further substituted with nonidentical atoms; if you have a rotable bond in a particular molecule then the molecule
shows different forms which are known as conformers or rotamers, we also said that
those rotamers some of them are stable like staggered and some of them are unstable like
eclipse, and between staggered and eclipse are infinite number of conformers; regarding
cyclic structures we can use small cycle like cyclopropyl which is rigid, cyclobutyl also
rigid; cyclopentyl undergo corner flapping; water does not have conformers while
peroxide has different conformers according to the definition of rotable bond.
We also explained the nature of this rotation as it rotates in very high speed 1012
rotation/second, yet we explained how the stability is related to abundance as the
compound stay in the most stable conformer (staggered, 90% chance to counter) for
longer time, and less time in the unstable conformer (eclipsed, 1% chance to counter).
L09.Medicinal Ch. 05.07.2015.Receptors
Regarding linear structures, if you observe the below figure, you'll notice why butane
has only one rotable bond; butane has 2 extreme conformers (eclipsed the most unstable;
staggered the most stable) between which there are infinite number of conformers.
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L09.Medicinal Ch. 05.07.2015
Husam A. Salamat
Sometimes, such as the case of ethylene glycol as observed with newman projection
below, you'll notice that the two hydroxyl are not staggered nor eclipsed to each other,
they are actually near to each and this conformer is known as skewed in which the 2 OH
form hydrogen bonds with each other making them stable. Therefore it's really hard to
predict whether a conformer is stable or unstable; but in general, the presence of
repulsion produces an unstable conformer (like eclipsed), the absence of repulsion
produces a stable conformer (like staggered), and sometimes you'll see H-bonds
stabilizing conformers (like skewed).
While cyclohexyl is totally flexible and has chair conformation and boat conformation; in
cyclohexyl chair conformer all Hs are staggered to each other making it the most stable
conformer, while in case of the boat conformer many Hs are eclipsed to each other
causing repulsion known as flag pauli repulsion making it the least stable conformer;
cyclohexyl is in continuous conversion between its conformers yet you'll find 90% in the
chair form while only 1% in the boat form, and the rest 9% as other conformers
according to stability-abundance relationship; other uncommon conformers of
cyclohexane such as skewed (twisted) conformation and half-boat conformation.
L09.Medicinal Ch. 05.07.2015.Receptors
Regarding cyclic structures we also have different conformers; the very short cyclic
structure like cyclopropyl is rigid allowing no conformational isomerism, cyclobutyl is
also rigid; but cyclopentyl is semi-rigid allowing corner movement called corner flapping
resulting in some conformational forms.
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L09.Medicinal Ch. 05.07.2015
Husam A. Salamat
Regarding cyclohexane chair conformation, if we had a bulk substitution like isopropyl, it
will have two different arrangements, either equatorial or axial; in general, equatorial
cyclohexanes are more stable than axial cyclohexanes if you have a bulky substituent;
because in case of axial an interaction will occur between H and isopropyl while Hs are
away in case of equatorial.
The important question to ask now, how does conformational isomerism affect biology?
Usually, a flexible molecule such as acetylcholine (shown below) it contains 2 rotable
bonds and tend to bind multiple receptors due to its conformational flexibility.
L09.Medicinal Ch. 05.07.2015.Receptors
To summarize...
Any structure bearing a rotable bond −either it's extended aliphatic or cyclic structure− is
expected undergo conformational isomerism and by doing so it generates different forms
of the same molecule; as you remember, in conformational isomerism there was no need
to break or form any bonds to convert one conformer to another (only movement), while
in optical isomerism we had to break and form bonds in order to convert an optical
isomer to another; we also discussed the stability-abundance relationship as a particular
compound spend more time in the stable conformer than the unstable conformer between
which there are infinite number of conformers.
For sure you should know the concept of conformational isomerism; you're requested to
revise them from organic chemistry and for any questions you're welcomed to ask the dr
in office.
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L09.Medicinal Ch. 05.07.2015
Husam A. Salamat
Having 2 rotable bonds in acetylcholine allows infinite number of conformational
isomerism which explains the ability of acetylcholine to bind around 15 different
receptors (Cholinergic receptors: Nicotinic and Muscarinic M1, M2, M3, M4, M5) in
addition the particular ligand for each receptor, whereas nicotinic receptors bind nicotine
and acetylcholine, while muscarinic receptors bind muscarine and acetylcholine, but
muscraine won't bind nicotinic receptor nor would nicotine with muscarinic receptors.
Look at the figure below, where eclipsed acetylcholine binds nicotinic receptors because
it's complementary with the receptor's binding pocket; while staggered acetylcholine
binds muscarinic receptors for the same reason.
If we look at Muscarine in the adjacent structure, the presence
of the ring will restrict it's rotation making it a rigid
compound that have been chosen by muscarinic receptor due
to its complementarily with its binding pocket.
One of the most advantages and disadvantages of flexible molecules that they tend to
bind multiple receptors; in nature, this is very convenient as single biosynthetic route
produces acetylcholine, and this acetylcholine has the ability to control many different
tissues in the body (skeletal muscles, smooth muscles, salivation, etc...); BUT in
pharmaceutical manufacturing this is actually a problem because higher flexibility will
cause side effects, which we don't want for sure.
L09.Medicinal Ch. 05.07.2015.Receptors
So, the point we're trying to clarify is that one of the results of conformational flexibility
is the ability of a ligand to bind multiple receptors because each receptor has its own
binding pocket that is complementary to certain conformation for that ligand. Imagine the
receptor is rotating in very high speed, what the receptor actually does is to capture the
compatible conformer of that ligand.
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L09.Medicinal Ch. 05.07.2015
Husam A. Salamat
The conformer that binds to a particular receptor is known as the pharmacophoric
conformer which means the conformer that provides the functional groups in such a way
it can bind to a particular receptor. For example, the pharmacophoric conformer of
nicotinic receptor is to put two compatible groups away from each other by 2.5A; or in
other words, the corresponding groups in the receptor binding pocket (anionic region and
the H-bond forming region) are 2.5A distance away from each other.
The first consequence -we've just discussed- for conformational flexibility is the ability
of a ligand to bind multiple receptors; the second consequence is the energetic issue.
In order to have ligand-receptor binding their should be topological match and attractive
interaction which is actually a result of the topological match as the interactions are
distance dependant (the absence of topological match lead to the absence of attraction);
those attractive interactions are called enthalpies which refer to the energy required to
break or form a particular interaction; a H-bond between OH and Oxygen requires 5 kilocalories/mole to break that bond, while a H-bond between -NH3 and -OH requires 2 kilocalories/mole to break that bond. So, the word enthalpy (∆H; heat content) refers to the
energy gain that you get by forming a particular interaction, or the energy required to
break that interaction. When we say that the enthalpy of H-bond is 5 kilo-calories/mole
we mean that I need 5 kilo-calories to break this bond, or I will gain 5 kilo-calories by
forming this bond.
The ligand-receptor binding is a cooperative process of a collection of enthalpies; if we
take the binding of epinephrine with its receptor as an example, the sum of interactions
enthalpies is what keeps epinephrine within the binding pocket; to know the collection of
enthalpy keeping epinephrine bound to the receptor we sum the contribution of each
interaction enthalpies
Total ∆H= ∆H of electrostatic attractions + ∆H of H-bonding + ∆H of Pi-Pi stacking
L09.Medicinal Ch. 05.07.2015.Receptors
The energetic issue
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L09.Medicinal Ch. 05.07.2015
Husam A. Salamat
If enthalpy values for each interaction were as shown above, then Total ∆H = 31, which
means that if you heat this complex by 31 kilo-calories/mole you'll actually break up the
complex. So, enthalpy or heat content or ∆H is the energy required to break the ligandreceptor complex or the energy required each individual interaction and separate the
ligand from its receptor; each individual interaction has its own enthalpy or its own heat
gain that is obtained or gained upon complexation, or required to break it down.
The ligand-receptor binding process consists of 2 important factors:
 Entropy, the energy gained due to disorder.
the force opposing enthalpy; for example, when you throw a glass cup on the ground it
will crash to small glass pieces, and if you collected the pieces trying to turn them back to
the original intact glass cup shape, the energy you spend is called entropic cost.
Entropic cost, is the energy spent to go against entropy. In the previous example the small
glass pieces is the stable form as the second law of thermodynamic states: entropy is a
driving force and a stabilizing factor; therefore to collect the pieces again you spend time
and effort which we called entropic cost, you'll pay a cost to overcome entropy.
Before binding happens, the ligand was free to move the following movements:
- Translational movement in X, Y, and Z dimensions.
which means, shifting position in all direction.
- Rotational movement in X, Y, and Z dimensions.
- Conformational movement in X, Y, and Z dimensions.
such as the case of acetylcholine we discussed previously.
L09.Medicinal Ch. 05.07.2015.Receptors
 Enthalpy, the energy gained of forming bonds, or required to break those bonds.
which is a result of topological match and the presence of attractive groups such as Hbond forming groups, Van Der Waals' forming groups and electrostatic groups.
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Husam A. Salamat
L09.Medicinal Ch. 05.07.2015
Those movements (translational, rotational and conformational) represent entropy; at the
moment the ligand enters the binding pocket it freezes and nearly stops moving; therefore
we go against entropy by stopping the ligand free movements (from disorder to order); so
binding itself has very important entropic cost that has to be paid.
So, enthalpy encourage binding and enhance the stability of the complex, while entropy
cost goes against enthalpy, which means that we are gaining energy by forming bonds but
in the other hand their are other forces that oppose this energy gain and disfavors binding.
Binding is a competition between 2 important factors; enthalpy factors which refers to the
strength of attractive interactions, and entropic factors which refers to the forces required
to go against entropy. In the same time you form interactions and encourage forming
complexes, there're some other forces that don't encourage complex formation which are
the entropic contribution, so they're required to fix the molecule inside binding pocket.
Back to the flexibility issue (the presence of rotable bond); each rotable bond costs
against binding by about 0.7 kilo-calories/mole; to further understand this, look at the
following equations:
(Gibbs fundamental equation)
In order for a chemical reaction to happen, ∆G must be -ve
which means that the sum of all enthalpies
(H-bond
enthalpy + electrostatic enthalpy + hydrophobic enthalpy)
must be higher than entropic cost
for binding to happen.

(Van't hoff's equation)
∆G: Gibbs free energy
∆H: enthalpy; heat gain
T: temperature
∆S: entropy
T∆S: entropic cost
R: gas constant
K: equilibrium constant

This equation explain that the relationship between the equilibrium constant (K) and the
energy (∆G) is exponential; which means that any minor increase in (↑∆G) result in a
major increase in (↑K); we can express it as following, each 1.5 kilo-calories gain in (∆G)
result in 1 log cycle (10 times) increase in equilibrium constant (K).
We know that each rotable bond costs around 0.7 kilo-calories/mole, then each 2 rotable
bonds (1.4 Kilo-calories/mole) result in a decrease in (K) by 1 log cycle which means 10
times decrease in K; so as you start with a certain amount of drug with certain potency, if
L09.Medicinal Ch. 05.07.2015.Receptors

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Husam A. Salamat
L09.Medicinal Ch. 05.07.2015
you add 2 rotable bonds to this drug, the potency will fall 10 times; you were giving the
drug as 1mg and now you must give it as 10 mg.
The presence of rotable bonds result in a decrease in the equilibrium constant (k) and a
decrease in affinity.
↑2 rotable bonds, ↓1 log cycle of K
CORRECTION
Carboxylic acid
(without EWD)
L09.Medicinal Ch. 05.07.2015.Receptors
 L04...
- Page 2, correct the bold word in the figure:
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