Lecture 4 - Lipinski Flashcards
What types of drugs does Lipinski’s rules apply to?
Orally administered drugs that are absorbed by passive mechanisms
Drugs that break the rules may still be useful if administered in other ways such as IV or topically
What are the 3 most important physiochemical properties with respect to drug design, and how are they measured?
Hydrophobicity - partition coefficient (p)
Electronic effects - Hammett substitution constant (sigma)
Steric effects - Hansch equation
What is the procedure for measuring the partition coefficient?
The drug is added to a separating funnel of water and octanol separated by a membrane
Only non-polar (hydrophobic) drugs can pass the membrane into the octanol
Drugs with a charge (e.g. a protonated amine group) cannot pass
Remove solvents and weigh amount of drug in each partition
The more hydrophobic a drug is, the more molecules will be in the octanol
What is the equation for the partition coefficient, and how would you interpret the value?
P = concentration of drug in octanol/concentration of drug in aqueous solution
Usually expressed as logP
High logP = more hydrophobic
How is the biological activity of a drug mathematically expressed?
C = concentration of drug required to achieve a defined level of biological activity
Usually expressed as 1/C
Higher 1/C value = Greater biological activity
When is logP negative?
When the compound is very hydrophilic
The p value is between 0 and 1
What are Lipinski’s ‘Rules of 5’?
An ideal drug has
Less than or equal to 5 hydrogen bond donors (OH and NH)
Less than or equal to 10 hydrogen bond acceptors (N and O)
A molecular weight of less than 500
A logP value of less than 5
What are Veber’s rules?
A drug will have good oral bioavailability when it has:
10 or fewer rotatable bonds
A polar surface area less than or equal to 140 Angstroms squared
The sum of hydrogen bond donors and acceptors is equal to or less than 12
Name 4 drug classes that violate Lipinski’s rules, and explain how they are still useful
Antibiotics
Antifungals
Vitamins
Cardiac glycosides
All either applied topically (antifungals) or act as a substrate for an active transporter in the GI tract
When might a compound with a molecular weight over 500 still have good oral bioavailability?
If it has reduced molecular flexibility and a constrained polar surface area
Why are natural products sourced from fungi, bacteria and plants usually exceptions to Lipinski’s rules?
They are usually structurally complex and have many stereoisomers
They rarely contain nitrogen (so less H bond acceptors)
They often make use of active transport mechanisms
They may have special conformational features that make them more able to undergo passive transport
What are the limitations of Lipinski’s rules?
All the rules have sharp boundaries, but realistically drugs that fail the rules slightly can still be useful
Equal weight is given to each rule, although realistically some rules can be more flexible than others e.g. logP is most important
How would you conduct an experiment to test if there is a relationship between the biological activity of a drug and it’s hydrophobicity?
Create many variants of the lead compound with slightly differing substituents
Calculate the partition coefficient for each compound
Measure the biological activity for each compound
Plot 1/C and logP on a graph and look for a correlation
How might you improve a drug that fails Lipinski’s rules?
Simplify the structure to reduce MW and remove any NH or OH groups
Cap any NH or OH groups with methyl/ethyl groups
