Rule of 5amd drug likeness

1. Good Morning

2. Dana Ameen
Pharmacy – HMU
28th FEB 2021

3. Lipinski's Rule of Five
• Lipinski's Rule of Five is a rule of thumb to evaluate
druglikeness, or determine if a chemical compound
with a certain pharmacological or biological activity
has properties that would make it a likely orally
active drug in humans .
ehT
elur
saw
detalumrof
yb
rehpotsirhC Lipinski in 1997 based on the
observation that most drugs are relatively small
and lipophilic molecules.

4. Lipinski's Rule of Five
• The rule describes molecular properties
important for a drug's pharmacokinetics in the
human body, including their absorption,
distribution, metabolism, and excretion "ADME“.
• However, the rule does not predict if a compound
is pharmacologically active.

5. Lipinski's Rule of Five
• The rule is important for drug development where a
pharmacologically active lead structure is optimized
step-wise for increased activity and selectivity, as well as
drug-like properties as described by Lipinski's rule.
• The modification of the molecular structure often leads
to drugs with higher molecular weight, more rings, more
rotatable bonds, and a higher lipophilicity.

6. Lipinski's rule says that, in general, an orally active drug has
no more than one violation of the following criteria:
• A molecular weight under 500 Daltons
• Not more than 5 hydrogen bond donors negortin(
ro
negyxo
smota
htiw
eno
ro
erom
negordyh
smota )
• Not more than 10 hydrogen bond acceptors
negortin(
ro
negyxo
smota )
• clog P of less than 5 (octanol-water partition
coefficient)
Note: all numbers are multiples of five, which is the
origin of the rule's name.

10. Lipinski Rule of 5
OH
OH O
N
OH
O
NH2
O
O
H
OH
H H
1. Molecular Weight < 500 Daltons
2. Log P < 5
3. < 10 Acceptor Groups (O+N)
4. < 5 Donor Groups ( O-H, N-H)
Tetracycline has MW 444
Tetracycline has 10 acceptors
Tetracycline has 6 donors

11. Lipinski Rule of 5
1. Molecular Weight < 500 Daltons
2. Log P < 5
3. < 10 Acceptor Groups (O+N)
4. < 5 Donor Groups ( O-H, N-H)
O
O
O
OH
OH
O
H
O
O
O
N
O
H
O
O
OH
Erythromycin has MW 734
Erythromycin has 14 acceptors
Erythromycin has 5 donors

12. Lipinski Rule of 5
1. Molecular Weight < 500 Daltons
2. Log P < 5
3. < 10 Acceptor Groups (O+N)
4. < 5 Donor Groups ( O-H, N-H)
O
N
H2
O
H
OH
NH2
O OH
O
O
H OH
NH2
NH2
O
O
N
H2
O
H
OH OH
O
Paromomycin has MW 616
Paromomycin has 19 acceptors
Paromomycin has 13 donors

13. Improvements
Over the past decade Lipinski's profiling tool for
druglikeness has led to further investigations by
scientists to extend profiling tools to lead-like properties
of compounds in the hope that a better starting point in
early discovery can save time dna cost.

14. Improvements
To evaluate druglikeness better, the rules have spawned
many extensions, for example one from a 1999 paper by
Ghose et al.
1. Partition coefficient log P in - 0.4 to + 5.6 range
2. Molar refractivity from 40 to 130
3. Molecular weight from 160 to 480
4. Number of atoms from 20 to 70

15. Biological activity and
homologous series

17. Biological Activity and
Homologous Series
The absolute and relative solubility of a drug in
aqueous and lipid phase of body are physical
properties of importance in providing and
maintaining effective concentration of the drug
at the site of action.
It have been shown that a regular changes in
biological activity is often near within
homologous series which provide a good
example to understand correlation of solubility
and partition coefficient with the drug action.

18. • For non ionized or slightly ionized molecule in
which change in structure (such as change in the
carbon chain) and graduation in intensity of
biological activity have been observed from a
number of pharmacologically unrelated groups or
compounds (e.g. resorcinol, estrogen and p-
amino benzoic derivative).

19. HO
OH
R
Alkyl resorcinol
Antibacterial
(Z)
R4
R3
R1
R2
Estrogen
Derivatives
NR'
R
Esters of PABA
COOH

20. Pharmacological
Activity
HO
OH
R
Alkyl resorcinol
Antibacterial

21. • In these homologous series the lower show a low
order of biological activity, but with increasing
logarithm of carbon chain, the biological activity
increases and further increase in carbon chain length
lead to sudden decrease (or sharp cutoff) in their
biological activity.
• While in vitro with increasing logarithm of carbon
chain, the biological activity increases, i.e. there will
be no sharp cutoff in killing staph or bacilli. bacteria.

22. HO
OH
R
Alkyl resorcinol
Antibacterial

23. Partition Coefficient and
General Anesthesia
➢Most of the substance commonly used as general
anesthetics, do not react chemically with any body
constituents, indeed the inert gas xenon can
produce anesthesia.
➢Theories attempting to explain the action of
anesthetics have therefore, emphasized physical
rather than chemical properties.
➢Overton-Meyer theory emphasized the close
correlation of lipid solubility of a substance with
its anesthetic potency.

24. Quantitative Structure Activity Relationship
QSAR
• QSAR studies is try to show that the gradual chemical
modification in the molecular structure of a drug will
produce important difference in its action.
• Therefore, it is established that the physiological action Φ
of a molecule is some function of its chemical
constitutions C, this can be expressed as: Φ = f (C)

25. Hansch Theory
• Hansch theory takes care of quantitative
relationship between drug distribution and
biological activity, depending on the base that the
biological activity is result of transition and
distribution of the drug in different compartments
(aqueous and lipid phase).

26. •(σ) means that the group has electron attracting character
(electron acceptor) it has great contribution to dissolve in polar
solvent.
(π) means electron donor (releasing) so has lipid solubility
contribution.
Group σ π
CH3 -0.17 + 0.51
H 0 0
CH3CONH2 + 0.1 - 0.79
Lipid
Soluble
Water
Soluble