Transcript Slide 1

Design of Small Molecule
Drugs Targeted to RNA
RNA Ontology Group
May 29 2007
Small Molecule and Large
Molecule Drug Design
• “Small Molecule” Drugs
– Low MW
– Moderately hydrophobic/hydrophilic
– Moderately chemical complexity
• “Biologicals”
– Peptides/peptidomimetics
– Engineered enzymes
– Antisense/RNAi
– Need help to enter cells!
“New Tools” for Drug Discovery
(1980s and 90s)
• Combinatorial Chemistry
Increased the number of available
compounds
• High Throughput Screening (“HTS”)
Increases throughput for testing (robotics,
databasing)
“It’s a Numbers Game”
Rational Drug Design = the
Opposite of “It’s a Numbers
Game”
Protein Structure
Design small molecule to “fit” and block active site
Voila!
Doesn’t work!
In Silico High Throughput Docking: A rational numbers game
Membrane Permeability & “DrugLikeness”
• The Lipinski
“Rule of Five”
Fragment Library Design
• Fragments must be “lead-like” not “druglike”
• MW < 250, allows compound to “grow”
• Weak binding affinity (will add affinity with
growth)
• Contain polar groups
– Insures solubility
– Polar groups are reactive
– Pick up hydrogen bonding interactions
• N fragments can cover the chemical space
of N2 compounds
Lipinski Rule of 5
•Molecular Weight < 500 Daltons
•cLogP < 5
•< 10 Acceptor Groups (O+N)
•< 5 Donor Groups ( O-H, N-H)
•Exceptions work by active transport
OH OH
HO
Thiostrepton
MW 1665
O
O
H 2N
N
NH 2
O
NH 2
OH
O
H 2N
OH
O
HO
NH 2
HO
OH
O
O
O
Paromomycin
MW 616
O
HO
O
O
OH
O
OHHO
HO
O
H
H
N
OH
OH
O
Erythromycin
MW 734
NH 2
OH O
OH O
OH
O
Tetracycline
MW 444
Examples of Small Molecule
Molders/Regulators of RNA
Secondary Structure in Bacteria
H
H
H
H
H
O
O
N
N
H
N
N
H
H
H
O
O H
H
O
S
H
N
N
N
H
N
N
SAM
Kd=20-200 nM
N
H
N
N
O H
N
O
O
N
N
SAH
No effect
H
N
N
N
N
H
2,6 diaminopurine
Kd=10 nM
H
H
H
N
N
H
N
S
H
H
O
H
H
O
Purine
Kd=100 µM
H
Examples of Small Molecule
Molders/Regulators of RNA
Secondary Structure in Bacteria
H
H
O
O
O P O
H
O
H O
O
H
H
O
H O
H
H
O
H
N
O
O
N
H
N
O
N
N
N
FMN
Kd=5 nM
H
N
N
H
O
Riboflavin
Kd=3 µM
O
H
H
H
N
H
N
O
H
O
H
O
O
N
L-Lysine
Kd=1 µM
H
H
N
H
D-Lysine
No effect
H
RNAbinding
Proteinbinding
a
b
Lipinski
druggable
c
Current Databases
• Pdb title search: RNA gets 2173 hits:
“ternary”
• Structure description search for ribonucleic
acid: 6 hits (2 DNA)
• NDB search for RNA + ligand: 841 hits,
including protein/RNA complex
• Most ligand databases oriented to search
for proteins/ligands
Database of RNA Binding
Compounds
• Antibiotics
• Riboswitch ligands
• Drug discovery programs (published)
• Published findings of natural products
• 105 compounds in all
Database of RNA Binding
Compounds (caveats)
• Only 25 compounds had pdb coordinates
• Reported Kd < 50 μM
• Redundancy: does not include near neighbors
• pdb coordinates did not identify noncontacting substructures
Database of RNA Binding
Compounds (further needs)
• DNA binding compounds
• Classification
• Correlation with RNA motifs/pharmacophores
HTS Paradigm
Fragment based
approaches
X
• >500k compounds screened
• assays usually require mM hits
• Template decoration often prevents interaction
• Need to reduce MW of weak binders prior
to modification
HTS requires “right” compounds in library
SeeDs Paradigm
(Structural Exploration of Exploitable Drug Startpoints)
•X-ray/NMR
•Chemistry
•SBDD
• Drug lead-like fragments
• No steric inhibition of scaffolds
• ~ mM binding
Grow potent, selective ligands from fragment