Lipinski rule of 5

Lipinski rule of 5
Also known as the Pfizer rule of 5 or simply the rule of
5 is a rule of thumb to evaluate drug likeness or
determine if a chemical compound with a certain
pharmacological or biological activity has chemical
properties and physical properties that would make it
a likely orally active drug in humans.
 HISTORY
Drug candidates are triaged early during drug development based on
computer modeling, high-throughput screening and cell-based assays
that predict pharmacologic activity. It is, however, much more difficult
to predict drug absorption, distribution, metabolism and excretion
(ADME), which typically require evaluation in vivo. Because in
vivo studies are slow and expensive, it is desirable to have simple
methods to predict ADME properties of drug candidates.
A widely accepted method to predict ADME properties is the Rule of
Five proposed by Lipinski in 1997. To develop this rule, Lipinski carried
out retrospective analysis of 2245 drugs at entry to Phase II, most of
which were orally active, lipophilic drugs, and identified which
physicochemical properties they had in common. The resulting
correlation identified four physicochemical parameters: molecular
weight (MW), number of H-bond donors (NHD), number of H-bond
acceptors (NHA) and octanol-water partition coefficient (log P).
The rule is important to keep in mind during drug discovery when a
pharmacologically active lead structure is optimized step-wise to
increase the activity and selectivity of the compound as well as to
ensure drug-like physicochemical properties are maintained as
described by Lipinski's rule. Candidate drugs that conform to the RO5
tend to have lower attrition rates during clinical trials and hence have an
increased chance of reaching the market.
 Components of the rule
Lipinski's rule of five:
• No more than 5 hydrogen bond donors (the total number of
nitrogen–hydrogen and oxygen–hydrogen bonds)
• No more than 10 hydrogen bond acceptors (all nitrogen or oxygen
atoms)
• A molecular mass less than 500 Dalton.
• An octanol-water partition coefficient (log P) that does not exceed 5
Note that all numbers are multiples of five, which is the origin of the
rule's name.
• Although “violation” of one rule may not result in poor absorption,
the liklihood of poor absorption increases with the number of rules
broken and extent to which they are exceeded
 variants
In an attempt to improve the predictions of druglikeness, the rules have
spawned many extensions, for example the Ghose filter:

• Partition coefficient log P in −0.4 to +5.6 range

• Molar refractivity from 40 to 130
• Molecular weight from 180 to 480
• Number of atoms from 20 to 70 (includes H-bond donors [e.g. OHs
and NHs] and H-bond acceptors [e.g. Ns and Os])
 Hydrogen bonds
• Hydrogen bonds increases solubility in water and must be broken in
order for the compound to permeate into and through the lipid
bilayer membrane.
• Thus an increasing number of hydrogen bonds reduces partioning
from the aqueous phase into the lipid bilayer membrane for
permeation by passive diffusion.
• HB donor: XH bond must be present
• HB acceptor: lone pair must be present
 Molecular weight
• molecular weight is related to the size of molecule.
• As molecular size increases the a larger cavity must be
formed in water in order to solubilize the compound and
solubility decreases.
• Incresing molecular weight reduces the compound
concentration at the surface of intestinal epithelium thus
reducing absorption.
• Incresing size also impedes passive diffusion through the
tightly packed aliphatic side chains of the bilayer
membrane.
 Partition coefficient log P
• The ratio of the equilibrium concentrations of
dissolved substance in two phase system containing
two largely immiscible solvents(water and octanol)
• Increasing logP also decreases aqueous solubility
which reduces absorption.
• log P= lipophilicity = absorption in lipid bilayer
P= [drug(octanol)/drug(water)]
• Log P predicts solubility, permeability, plasma
binding, absorption
 Examples of drugs
DOXORUBICIN
Hydrogen bond donor = 7
Hydrogen bond acceptor= 12
Molecular weight = 534g/mol
Log P = -1.7
Bioavailability of approximately= 5%.
Doxorubicin has very low oral
Bioavailability as depicted by
Lipinski rule of 5.
 Acyclovir
Calculated physicochemical properties

1. Hydrogen bond donors 4

2. Hydrogen Bond Acceptor 8

3. Molecular weights 225g/mol

4. Log P -1

5. No. of Lipinski rule broken 0

Amlodipine:
Paracetamol:
Aspirin
Artemisnin
Omeprazole