biochemistry sixth edition bonus chapter: drug development copyright © 2005 by w. h. freeman and...
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BiochemistrySixth Edition
Bonus Chapter:Drug Development
Copyright © 2005 by W. H. Freeman and Company
Berg • Tymoczko • Stryer
Know “ADME”
• Administration - Absorption• Distribution in the body• Metabolism - Transformation• Excretion
Lipinski’s Rules
• 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!
Know structures of conjugates
• Glutathione (ECG) via -SH• Glucuronides from UDP-Glucuronic
• Sulfate from PAPS (A-stick 3’P, 5’PS)
Drug design for known target
Becoming more important. Once a drug is known,
variants can be screened for activity. Some HIV protease inhibitors:
Co-crystal structure of Arachidonic acid(ball and stick) and Cox-1. The TYR andARG stabilize the carboxylic acid. TheILE and the Aromatic Wall hem theArachidonic acid into the binding site.
ARG
ILE
TYR
SER
Aromatic Wall
O
O
Arachidonic Acid
ARG
ILE
TYR
SER
Aromatic Wall
Model of Aspirin (ball-and-stick) and Cox-1.The SER residue on the enzyme has attacked the aspirin, hydrolyzing theacetyl group and irreversibly inactivatingthe enzyme.
O O
O
O
O
O O
O HO
O
Enz
+
Enz
AcetylGroup
Salicylic Acid
Practical Guide to Identifying Non-Selective vs Selective Cox Inhibitors
O
O
O
O
O
N
O
O
O
O
Cl
NH
OO
O
it appears thatmost non-selective Cox inhibitors share the following lineararrangement of functional groups:
Greasy Aryl Alkyl Acidic
Indomethacin
Ibuprofen
Ketoprofen Etodolac
Med chemists can use this SARto guide the development of newer, better (hopefully) non-selective Cox inhibitors.
Practical Guide to Identifying Non-Selective vs Selective Cox Inhibitors
NN
Br
SNH2 O
O
F
F
F
O
S
O
O
O
ON
SNH2 O
O
NN
S
O
OCl
Most Cox-2 selectiveinhibitors are shaped likean arrowhead:
Greasy
Side chain(usually sulfonamideor sulfonyl)
Aryl
Polar
The SAR for non-selective Coxinhibitors is clearly different fromCox-2 selective inhibitors. Med chemistscan exploit this fact to design novel compounds.
rofecoxib valdecoxib
Like celecoxib, exceptBr is Me group etoricoxib
Analyzing Genomic Information
Known targets (Protein Kinases or 7TM receptors = GPCR) can suggest new
drugs.