Biochemistry Sixth Edition Bonus Chapter: Drug Development Copyright © 2005 by W. H. Freeman and...
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Biochemistry Sixth Edition Bonus Chapter: Drug Development Copyright © 2005 by W. H. Freeman and Company Berg • Tymoczko • Stryer
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Transcript of Biochemistry Sixth Edition Bonus Chapter: Drug Development Copyright © 2005 by W. H. Freeman and...
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!
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:
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.
Model Animals also yield targets
Knockout mice tell us about interesting genes/proteins
