Berg • Tymoczko • Stryer
Biochemistry
Sixth Edition
Bonus Chapter:
Drug Development
Copyright © 2005 by W. H. Freeman and Company
Know “ADME”
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Administration - Absorption
Distribution in the body
Metabolism - Transformation
Excretion
Lipinski’s Rules
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MW should be less than 500
H-bond donors less than 5
H-bond acceptors less than 10
Partition coefficient less than 5
• Otherwise drug will have poor absorption!
From HW, mol wt = 604
Know structures of conjugates
• Glutathione (ECG) via -SH
• Glucuronides from UDP-Glucuronic
• Sulfate from PAPS (A-stick 3’P, 5’PS)
Serendipity
Drugs discovered accidentally
Screening
Compare activities of large libraries
of drugs. SAR structure activity
relationships
Cholesterol Lowering Drugs
Statins found by screening
Drug design for known target
Becoming more important. Once a
drug is known, variants can be
screened for activity. Some HIV
protease inhibitors:
TYR
SER
Aromatic Wall
ILE
ARG
Co-crystal structure of Arachidonic acid
(ball and stick) and Cox-1. The TYR and
ARG stabilize the carboxylic acid. The
ILE and the Aromatic Wall hem the
Arachidonic acid into the binding site.
O
O
Arachidonic Acid
TYR
Salicylic Acid
SER
Aromatic Wall
ILE
Acetyl
Group
Model of Aspirin (ball-and-stick) and Cox-1.
The SER residue on the enzyme has
attacked the aspirin, hydrolyzing the
acetyl group and irreversibly inactivating
the enzyme.
ARG
Enz
O
O
O
O
Enz
O
O
O H
O
O
+
O
Practical Guide to Identifying Non-Selective vs Selective
Cox Inhibitors
it appears that
most non-selective Cox inhibitors
share the following linear
arrangement of functional groups:
O
O
O
O
N
O
Cl
Ibuprofen
O
Indomethacin
Greasy
Aryl
Alkyl Acidic
Med chemists can use this SAR
to guide the development of
newer, better (hopefully) nonselective Cox inhibitors.
H
N
O
O
O
O
Ketoprofen
O
Etodolac
O
Practical Guide to Identifying Non-Selective vs Selective
Cox Inhibitors
Most Cox-2 selective
inhibitors are shaped like
an arrowhead:
O
N
O
Greasy
O
O
Aryl
O
S
H2N
Orofecoxib
S
valdecoxib
O
Polar
Br
Side chain
(usually sulfonamide
or sulfonyl)
N
N
F
N
F
N
F
O
S
The SAR for non-selective Cox
H2N
O Like celecoxib, except
inhibitors is clearly different from
Br is Me group
Cox-2 selective inhibitors. Med chemists
can exploit this fact to design novel compounds.
Cl
O
S
O
etoricoxib
Analyzing Genomic Information
Known targets (Protein Kinases or
7TM receptors = GPCR) can suggest
new drugs.
Model Animals also yield targets
Knockout mice tell us about
interesting genes/proteins